non-invasive cardiovascular risk assessment › wp-content › uploads › ... · overall cv risk,...
TRANSCRIPT
Non-invasive cardiovascular risk assessment
The AGE Reader provides an immediate prediction for the cardiovascular risk of your patient. The non-invasive and extensively validated AGE Reader is and ideal tool for point of care testing. The measurement result is available in 12
seconds and can be exported directly.
Glucose
Protein
Schiff Bases
AmadoriProducts
Advanced GlycationEndproducts
ReactiveIntermediates
Measuring AGEsWith any other measurement it has been complicated
to measure tissue AGEs in patients because they are
expensive, time consuming, lack specificity, are poorly
reproducible and/or are invasive. The AGE Reader is
the answer to the need for measuring AGEs without
the disadvantages of the existing methods. This
state of the art device provides a simple non-invasive
solution, which allows clinicians to determine the AGE
level within 12 seconds.
Many advanced glycation endproducts (AGEs) have a
characteristic fluorescence. Moreover, tissue fluores-
cence in (invasive) biopsies has an established as-
sociation with chronic complications. The AGE Reader
is able to easily, quickly and noninvasively measure
AGEs by means of fluorescence techniques1.
About AGEs (Advanced Glycation Endproducts)
AGEs are the result of a chain of chemical reactions
(the Maillard reaction) after an initial glycation. AGEs
normally accumulate slowly over a person’s lifetime
in tissues with slow turnover. But this process oc-
curs more rapidly in patients with conditions such as
diabetes mellitus, renal failure and cardiovascular
disease. AGEs also accumulate rapidly under circum-
stances of oxidative stress. These accumulated AGEs
play a key role in the development of diabetes and its
complications. The level of AGEs in tissue reflects the
glycometabolic memory and is a valuable predictor of
cardiovascular events and (pre)diabetes.
Clinical useClinical professionals have been successfully using
the AGE Reader in their clinics for over 10 years.
The AGE Reader is the answer to the need to quickly,
reliably and non-invasively measure the cardio-
vascular risk of your patient.
The AGE Reader assists clinical professionals in
identifying patients with an increased cardiovascular
risk. This helps clinicians to decide whether a change
in treatment is needed.
AGE ReaderThe AGE Reader provides an immediate prediction for
cardiovascular risk. The measurement is reliable, real
time, non-invasive and easy to use.
Moreover, the AGE Reader has been validated in clini-
cal studies around the world. The AGE Reader has
been used in clinical practice and research since 2006
in over 1000 clinics worldwide. Since the introduction
of the AGE Reader more than 200 peer reviewed pa-
pers have been published. These papers give an over-
view of clinical studies in diabetes2, cardiovascular
disease3 and renal disease4.
Clinical validationKey conclusions of the clinical validation
studies using the AGE Reader:
• Reflects vascular damage in the diabetes
patients2.
• Identifies diabetic patients at risk of developing (car-
diovascular and microvascular) complications5,6,7.
• Predicts the risk of having or developing diabetes
and the metabolic syndrome8,9.
• Strong predictor of major cardiovascular events in
peripheral artery disease10.
Type 2 Diabetes population (n=987)
2.0Measurement
result 2.25 2.5 2.75 3.0 3.25
Microvascular andmacrovascularcomplications
Type 2 Diabetessubgroups
Mean AF in the totalT2DM population
Mean AF with 95% CIin healthy subjects
Macrovascularcomplications
Microvascularcomplications
No complications
* References can be found on the back
This non-invasive and convenient measurement
can be performed by any clinical professional
and is completed within 12 seconds.
Name:
Date of birth:Age:
Gender:
Patient ID:
Exame date:
Physician:
John Doe
01-02-1975
40male001
11-09-2015
Diagnoptics
Cardiovascular Risk Report
Excellent Verygood
Good Fair Poor
Previousresults
Currentresults
AGE Reader result
The AGE Reader measurement result is 2.9 or above. This indicates a
definitely high cardiovascular risk. It is recommended that other
cardiovascular risk factors should be assessed and treated, with low
threshold and target values for starting or intensifying treatment.
Planning
Previous visit
11-09-2015
Current visit
11-09-2015
Next visit
11-10-2015
EASD
Stockholm-
Cardiovascular Risk Report
Cardiovascular risk factors are conditions or habits that raise
your risk of cardiovascular disease and events. There are
traditional and innovative cardiovascular risk factors known.
This cardiovascular risk report provides an overview of
selected cardiovascular risk factors with special attention for
the AGE Reader measurement result.
Risk FactorPrevious 11-09-2015
Measurement results
Current 11-09-2015
AGE
Smoker
Diabetes
LDL cholesterol
HDL cholesterol
Systolic blood pressure
2.9
Yes
Yes
135
43
160
2.0
Yes
Yes
138
45
160
2.9
Name:
Date of birth:Age:
Gender:
Patient ID:
Exame date:
Physician:
Jane Doe
10-10-1980
34female
002
11-09-2015
Diagnoptics
Cardiovascular Risk Report
Excellent Verygood
Good Fair Poor
020
40
No
increased
CV risk
Risk group 1:
Limited increase
of CV risk
Risk group 3:
Definite
CV riskRisk group 2:
Increased
CV risk
6080
1
2
3
4
5
Age (years)
Measurement results
Current 11-09-2015
AGE Reader result
The AGE Reader measurement result is above 1 standard deviation of the age
related mean. This indicates an increased cardiovascular risk. Depending on
overall CV risk, lifestyle or pharmaceutical treatment should be considered.
Planning
Previous visit
-
Current visit
11-09-2015
Next visit
11-10-2015
EASD
Stockholm-
Cardiovascular Risk Report
Cardiovascular risk factors are conditions or habits that raise
your risk of cardiovascular disease and events. There are
traditional and innovative cardiovascular risk factors known.
This cardiovascular risk report provides an overview of
selected cardiovascular risk factors with special attention for
the AGE Reader measurement result.
Risk FactorPrevious
-
Measurement results
Current 11-09-2015
AGE
Systolic blood pressure
2.3
150
-
-
2.3
Diagnoptics Technologies B.V.
www.diagnoptics.com
www.age-reader.com
Address:
Aarhusweg 5-9
9723 JJ Groningen
The Netherlands
Contact details:
P +31 50 589 06 12
F +31 50 589 06 13
The AGE Reader App
Export the measurement directly to the AGE Reader
App using the Bluetooth connection and add other
cardiovascular risk factors to generate a comprehen-
sive Cardiovascular Risk Report. For each patient all
visits can be documented and consulted in the easy
to use App. The Cardiovascular Risk Report can simply
be printed, saved and shared.
Download the AGE Reader App free of charge on
www.diagnoptics.com. Available for:free of charge on
www.diagnoptics.com
Explain & Motivate patients
The graphical display allows you to combine the AGE
Reader result with desired other cardiovascular risk
factors and explain the results to patients. A hardcopy
of the report can be handed to the patient, which will
make it easier to understand the measurement result
and the associated cardiovascular risk.
Windows OS X
References
1. Meerwaldt R. et al. Diabetologia. 2004; 47(7): 1324:1330.
2. Lutgers H. et al. Diabetes Care. 2006; 29(12): 2654-2659.
3. Hofmann B. et al. Exp Gerontol. 2012 Epub May 12.
4. McIntyre N. et al. Clin J Am Soc Nephrol. 2011 Oct;6(10):2356-63.
5. Lutgers H. et al. Diabetolgia, 2009; 52(5): 789-797.
6. Gerrits E. et al. Diabetes care. 2008; 31(3): 517-521.
7. Noordzij M. et. Diabet Med. 2012; 29(12): 1556-1561.
8. Van Waateringe et al. Diabetol Metab Syndr. 2017 May 30;9:42
9. Oral and poster presentations EASD 2017. Submitted for publication
10. De vos L. et al. Arterioscler Thromb Vasc Biol. 2014 Apr;34(4):933-8
Please visit www.diagnoptics.com/age-reader for a complete overview of all AGE Reader publications.
AGEs DamAGE Our Bodies. (Advanced glycation end-products)
By Brady Hartman in Anti-Aging Science, Healthy Living October 19, 2017
Sharing is caring!
Reading Time: 11 minutes. >>
Summary: AGEs (advanced glycation end-products) are in the spotlight again
as geroscientists implicate this toxic waste of our bodies in a multitude of health
conditions, including inflammaging, cancer, and diabetes. Some scientists go as far as
to link AGEs to an increase in the chronic inflammation which leads to heart
attacks. [This article first appeared on
the website LongevityFacts.com. Author: Brady Hartman. ]
Executive Summary
Are advanced glycation end-products (AGEs) a villain that causes chronic diseases or
are they merely an innocent bystander?
Anti-aging scientists are coming to the growing conclusion that AGEs play a
significant role in inflammation and the chronic diseases of aging, such as diabetes,
heart disease, and many others. Furthermore, some geroscientists suspect that AGEs
significantly contribute to cancer.
In an earlier review that links AGEs with cancer, David P. Turner, a researcher with
the Department of Pathology & Laboratory Medicine at the Medical University of
South Carolina in Charleston (MUSC) sums it up by saying,
“Advanced glycation end-products (AGEs) are reactive metabolites
produced as a by-product of sugar metabolism. Failure to remove these
highly reactive metabolites can lead to protein damage, aberrant cell
signaling, increased stress responses, and decreased genetic fidelity.”
Earlier this year, Turner updated his research on the link between advanced glycation
end-products and cancer, as you will read later on.
Turner and other researchers are adding to the growing body of evidence against
AGEs. Geroscientists are sure that the steps we take to reduce AGEs are incredibly
good for our health. That is, having low blood sugar, low cholesterol levels and eating
less processed foods are sure-fire ways to lengthen our lives and coincidently also
reduce advanced glycation end-products.
Bottom Line: AGEs are bad for our health. However, scientists don’t know the exact
extent. There is hope, however. Scientists have come up with ways to prevent the
build-up of advanced glycation end-products.
AGEs DamAGE Our Bodies
What Scientists Know About AGEs
Turner is not the only geroscientist accusing AGEs of misconduct. Other researchers
already know that advanced glycation end products naturally build up in our bodies as
we grow older, although the things we eat can also increase their levels. Geroscientists
show that AGEs raise the level of cellular damage, which in turn increases the levels
of chronic inflammation. Aging is accompanied by a chronic low-level inflammation
called inflammaging that affects nearly every cell in the body. Moreover, as you will
read later on, they have the evidence to back it up. As well, leading geroscientists,
such as Carlos Lopez-Otin, the author of the landmark report The Hallmarks of Aging,
believe that the chronic inflammation significantly contributes to the progression of a
slew of chronic diseases.
Strong Suspicions About AGEs
Many researchers have indicted AGEs as a major villain in chronic diseases with an
inflammatory component such as asthma, atherosclerosis, arthritis, cancer, heart
disease, kidney disease, blindness, and neuropathic pain. While geroscientists are
confident that advanced glycation end products increase levels of chronic
inflammation, and contribute to a handful of chronic diseases, they are not quite sure
how large of a role AGEs play in these conditions.
Bad habits such as a high-fat, high-sugar diet simultaneously lead to both increased
incidences of these chronic diseases as well as increased levels of advanced glycation
end products. Whenever any one of these chronic diseases strikes, large numbers of
AGEs are always at the scene of the crime.
Bottom Line: There is a growing consensus that AGEs are responsible for vandalism
to our bodies, increase inflammaging and stoke the fires of chronic diseases.
How advanced
glycation end-products form (AGEs). Credit: David Turner (2017)
It’s So Easy to Get Glycated These Days
AGEs are a diverse array of compounds produced in the body through a variety of
chemical reactions. In a process called glycation, AGEs form when sugars combine
with proteins or fats. When sugar latches on to one of these molecules, it creates what
is known as an advanced glycation end-product.
For example, consider a lab test called the hemoglobin A1c test. If you have ever been
tested for diabetes or prediabetes, then you are probably aware of the A1c test. This
common diagnostic for diabetes measures the blood levels of an advanced glycation
end-product called glycated hemoglobin. As an aside, if you are over 45 or overweight,
the ADA says you ought to get tested for prediabetes and diabetes.
The A1C test also abbreviated HbA1c, and HbgA1c is a blood test that measures a
person’s average blood sugar levels over the past three months. To keep us even more
confused, doctors use a multitude of names, such as glycohemoglobin, glycated
hemoglobin, and glycosylated hemoglobin to all refer to the same compound.
Whatever you want to call it, glycated hemoglobin is a common AGE in your
bloodstream. Glycosylated hemoglobin forms when sugar chemically attaches to
hemoglobin. The more sugar in your blood, the more glycated hemoglobin, and the
higher your A1c reading. The higher your A1c level, the more likely your doctor will
diagnose you with prediabetes or diabetes.
What Increases Advanced Glycation End-Products?
AGEs are more likely to form when blood sugar is elevated, which explains the higher
levels of advanced glycation end-products in people with poorly controlled type 2
diabetes. People also consume advanced glycation end-products, mostly from cooked
or processed foods, and absorb them from tobacco smoke. The body can eliminate
AGEs using enzymes and expel them via the kidneys, but the advanced glycation end-
products formed in the body are more likely to accumulate.
With a toaster, anyone can make advanced glycation end-products (AGEs) at home.
Just brown the crust. Credit: StockSnap
Who Discovered AGEs?
In 1912 a French scientist named Louis-Camille Maillard discovered how AGEs form
in food. Maillard was the first to explain the chemical reaction – subsequently named
the Maillard reaction – results from the browning of certain foods when cooked, such
as bread crust and meat. Scientists have researched AGEs for the past 20 years, and
are increasingly focused on food sources of these compounds.
Why Do Advanced Glycation End-Products Form?
Advanced glycation end-products build up naturally in the body as we grow older.
While high blood sugar is the main culprit, high cholesterol also accelerates the build
of AGEs. We get advanced glycation end-products through our diet, as well.
Components of certain foods called dietary advanced glycation end-products (dAGEs)
contribute to the levels of AGEs in our body and also increase the risk of diseases such
as kidney disease and atherosclerosis. Scientists do not fully understand how well the
AGEs we consume from foods are absorbed by the gut, nor whether vitamins and
other nutrients influence their effects on the body.
Advanced Glycation End-Products and Diabetes
Scientists strongly suspect that advanced glycation end-products are involved in the
progression of diabetes and the complications of the disease.
In diabetics, uncontrolled blood sugar leads to higher risks of all kinds of
complications, including heart disease, stroke, kidney disease, amputations, and
blindness. Scientists have not conclusively fingered AGEs as the culprit behind these
complications, but in my book, they are the number one suspect.
Research on Advanced Glycation End-Products
The strongest research evidence studies the effects of AGEs in humans. However, a
research experiment in which scientists fed a diet high in AGEs to mice is very telling.
Lab animals are easier to test AGEs on because they develop diseases more quickly.
Credit: Tibor Janosi Mozes
Dietary AGEs Induce Diabetes in Mice
While human studies are far more reliable, mouse studies can add insight because
researchers can do things to mice that would be unethical to humans. Furthermore,
mice develop diseases much faster than humans, who take decades to develop chronic
disease. For example, in a study published in Diabetes, the journal of the American
Diabetes Association, a team of researchers at New York’s Mount Sinai Medical
Center (MSMC) fed lab mice a diet high in AGEs and compared them to normally fed
controls. The MSMC researchers found that the mice on a diet high in dietary AGEs
were significantly more like to develop diabetes when compared to controls. The
researchers divided the mice into three groups: a) a high-fat diet high in AGEs b) high-
fat diet low in AGEs c) normally fed control mice.
After waiting for six months, the human equivalent of 34 years, 75% of the mice on
the high AGE diet developed diabetes, while none of the mice on the low AGE diet
developed the condition. The mice on the two high-fat diets gained similar amounts of
body weight.
Bottom Line: Researchers showed that, at least for mice, fat is not to blame for
causing diabetes, instead of advanced glycation end-products are responsible.
Testing AGEs (advanced glycation end-products) in people gives the best results.
Credit: RawPixel
Human Study On Advanced Glycation End-Products
In a study published in the journal Diabetologia in 2016, researchers at New York’s
Mount Sinai Medical Center (MSMC) analyzed the role of AGEs and the risk of type
2 diabetes. The MSMC researchers randomized 61 obese people with metabolic
syndrome into two groups: Half ate a diet low in AGEs while the other half ate a
standard American diet that was high in advanced glycation end-products. The
participants on the low-AGE diet were told to avoid grilling, baking, or frying food to
reduce consumption of advanced glycation end-products. After one year, the group on
the low AGE diet had lower blood levels of advanced glycation end-products, a
reduction in insulin resistance, a decrease in markers of inflammation and oxidative
stress, and a small amount of weight loss to boot.
AGEs and Insulin Sensitivity in Humans
Similarly, in a small Australian study published in the American Journal of Clinical
Nutrition in 2016, healthy overweight people were put on a low AGE diet low for two
weeks. At the end of the study period, the participants on the diet low in AGEs had
improved insulin sensitivity compared to those on a diet high in advanced glycation
end-products.
Do AGEs cause diabetes? The evidence against advanced glycation end-products is
compelling. Credit: Tesa Robbins.
Do AGEs Cause Diabetes?
The levels of advanced glycation end-products in our bodies increase as we age, and
the rates of diabetes rise correspondingly. In fact, by the age of 65, two-thirds of all
American adults have either diabetes or prediabetes. Correlation does not imply
causation, but it sure is a hint. The correlation combined with the animal and human
research studies strongly argue that AGEs make us significantly more susceptible to
prediabetes and type 2 diabetes.
Prediabetes is the condition where a person has high blood sugar, but not high enough
to be considered diabetes. The World Health Organization (WHO) estimates that
prediabetes kills one and half times as many people as diabetes because it is far more
prevalent and far more undetected than diabetes.
This is a great tragedy due to that fact that prediabetes can be treated by a diet and
exercise, or medication. Coincidentally, the drug metformin, the same medication that
doctors use to treat prediabetes and diabetes is also a lifespan-extension drug.
Cardiovascular Disease of the AGEs
Scientists strongly suspect that AGEs stoke the disease of atherosclerosis. In turn,
atherosclerosis, also called hardening of the arteries, leads to cardiovascular disease
and heart attacks. An earlier report links inflammation to heart disease.
Cancer of the AGEs
Researcher David Turner has sharpened his pencil as of late. This year (2017) Turner
published an updated review of the role of AGEs in cancer in the journal Advances in
Cancer Research. In this special compendium on cancer, which includes the works of
many other researchers, Turner makes a stronger case for a role of AGEs in cancer,
saying
“Due to their links with lifestyle and the activation of disease-associated
pathways, AGEs may represent both a biological consequence and a bio-
behavioral indicator of poor lifestyle which may be targeted within specific
populations to reduce disparities in cancer incidence and mortality.”
AGEs in Alzheimer’s Disease
As we grow older, AGEs accumulate in the brain and other tissues. Researchers have
implicated advanced glycation end-products in cultured neuronal toxicity as well as
beta-amyloid aggregation in Alzheimer’s disease.
Cleaning out Advanced Glycation End-Products
Medical science has yet to invent a magic pill or potion that cleans a significant
portion of AGEs from the body. Prevention is your best bet, and keeping your blood
sugar low is a proven way to prevent a ton of chronic diseases, including cancer, heart
disease, and diabetes.
For example, consider glucosepane, by far the most common AGE in human
tissue. Glucosepane forms cross-links in the collagen of our arteries and joints, causing
them to become stiffer. As we age, the level of glucosepane in our collagen increases,
leading to arteriosclerosis and joint stiffening. Due to decades of elevated blood sugar
levels, this effect is accentuated in people with diabetes.
To reverse aging, geroscientists are searching for compounds that reverse cross-linking
and return our joints and arteries to their youthful, supple state. Researchers that they
had found such a substance with the discovery of a compound called alagebrium
(ALT-711.)
ALT-711 produced seemingly miraculous effects in aging and diabetic lab animals and
substantially lowered their blood pressure. However, alagebrium was a disappointment
when tested on humans, producing only minor effects.
If we are to reverse aging, research on glucosepane is sorely lacking and sorely
needed. Reason at fightaging.org has a good description of the subject, as well as
a recent update on the efforts of researchers developing monoclonal antibodies that
attack glucosepane.
Bottom Line: There are no adequate cleaning products to get rid of advanced
glycation end-products.
All-beef patty and AGEs on a sesame seed bun. Advanced glycation end-products are
highest in meat, especially flame-broiled. Credit: Robert Owen-Wahl.
Reducing AGEs in Food
AGEs occur naturally in many foods, especially animal-derived products, such as
meats that are rich in fat and protein. The level of advanced glycation end-products in
food depends on how you cook or prepare it. High temperatures produce more
advanced glycation end-products, but AGEs can also be found in aged cheeses (no pun
intended). As well, specific processes used by food manufacturers to add flavor or
color to their products also boost advanced glycation end-products.
Compared to low-heat methods, more advanced glycation end-products form when
cook meat with dry-heat methods, including roasting, grilling, frying, or baking. All
of these methods cook at relatively high temperatures and for longer times than the
low-heat methods. Low-heat methods produce the lowest levels of AGEs and include
boiling, steaming, poaching, or stewing. As well, low-heat methods retain food
moisture. Microwaving produces fewer advanced glycation end-products because of
its relatively short cooking times. The source of animal protein also affects the
generation of AGEs, with beef having the most, and fish the least. The fat content in
meat tends to contain more advanced glycation end-products. Marinating meat with
acidic preparations such as lemon juice and vinegar inhibits advanced glycation end-
product formation.
On the flip side, fruits and vegetables are not only healthy, but they are also low in
AGEs, even when cooked. As well, many grains are lower in advanced glycation end-
products. However, grain products such as cookies, crackers, and chips are higher in
AGEs because they are processed with dry heat methods and loaded with additional
fats and sugars. Despite this, when compared to meat, processed grain products such as
potato chips have a lower content of advanced glycation end-products. Potatoes are a
healthy vegetable, unfortunately, frying them boosts their levels of AGEs.
Bottom Line
AGEs are bad for our health. However, scientists do not know the precise extent.
Geroscientists need to perform more research to fully understand the health effects of
advanced glycation end-products, including both those produced by the body and those
we consume from foods. Meanwhile, what we know about AGEs does not change our
thinking about healthy eating. Recent research reports have given us good reasons to
limit fatty meats, especially those cooked with high heat, a process that produces
carcinogens such as heterocyclic amines. As well, doctors advise us to limit fried or
highly processed foods such as French fries and chips. Moreover, so-called heart-
healthy eating patterns, such as the Mediterranean diet, are low in advanced glycation
end-products. Also, low AGEs diets are those low in processed foods, meat and fast
foods and rich in fruits and vegetables, legumes, whole grains, fish, and low-fat dairy.
Show Us Some Love
1. One click helps us spread the word – Share this post on your social media
account and help your friends. It only takes one click on any of the social media
links on this page.
2. Follow us on social media – For weekly articles, follow us
on Facebook | Reddit | Google+.
3. Sign up for our email list – We use your email to notify you of new articles. We
don’t spam and we don’t share your email address. Cancel at any time.
4. Tell us what you think – We want to hear what you think. Scroll down to leave
your comments below.
References
Turner, David P. “Advanced Glycation End-Products: A Biological Consequence of
Lifestyle Contributing to Cancer Disparity.” Cancer Research 75.10 (2015): 1925–
1929. PMC. Web. 17 Oct. 2017. Link to Article.
Carlos López-Otín, et al. “The Hallmarks of Aging.” Cell, Volume 153, Issue 6, 1194
– 1217 (2013). Available Online.
Oana Sandu, Keying Song, Weijing Cai, Feng Zheng, Jaime Uribarri, Helen Vlassara.
“Insulin Resistance and Type 2 Diabetes in High-Fat–Fed Mice Are Linked to High
Glycotoxin Intake.” Diabetes Aug 2005, 54 (8) 2314-2319; DOI:
10.2337/diabetes.54.8.2314. Link to Article.
D.P. Turner, Chapter One – The Role of Advanced Glycation End-Products in Cancer
Disparity, Editor(s): Marvella E. Ford, Dennis K. Watson, In Advances in Cancer
Research, Academic Press, Volume 133, 2017, Pages 1-22, ISSN 0065-230X, ISBN
9780128098783, https://doi.org/10.1016/bs.acr.2016.08.001. Alternate Link.
Disclaimer
Diagnosis, Treatment, and Advice: This article is intended for educational and
informational purposes only and is not a substitute for professional medical advice. The
information and opinions provided herein should not be used during any medical emergency
or for the diagnosis or treatment of any medical condition. Experimental therapies carry a
much higher risk than FDA-approved ones. Consult a licensed and qualified physician for the
diagnosis and treatment of any and all medical conditions. Call 911, or an equivalent
emergency hotline number, for all medical emergencies. As well, consult a licensed physician
before changing your diet, supplement or exercise programs. Photos, Endorsements, &
External Links: This article is not intended to endorse organization, companies, or their
products. Links to external websites, mention or depiction of company names or brands, are
intended for illustration only and do not constitute endorsements.
van Waateringe et al. Diabetol Metab Syndr (2017) 9:42 DOI 10.1186/s13098-017-0241-1
RESEARCH
Skin autofluorescence, a non-invasive biomarker for advanced glycation end products, is associated with the metabolic syndrome and its individual componentsRobert P. van Waateringe1*, Sandra N. Slagter1, Andre P. van Beek1, Melanie M. van der Klauw1, Jana V. van Vliet‑Ostaptchouk1, Reindert Graaff1, Andrew D. Paterson2, Helen L. Lutgers3 and Bruce H. R. Wolffenbuttel1
Abstract
Background: The metabolic syndrome (MetS) comprises several cardiometabolic risk factors associated with increased risk for both type 2 diabetes and cardiovascular disease. Skin autofluorescence (SAF), a non‑invasive bio‑marker of advanced glycation end products accumulation, is associated with cardiovascular complications in subjects with diabetes. The aim of the present study was to examine the association between SAF and the presence of MetS as well as its individual components in a general population.
Methods: For this cross‑sectional analysis, we included 78,671 non‑diabetic subjects between 18 and 80 years of age who participated in the LifeLines Cohort Study and had SAF measurement obtained non‑invasively using the AGE Reader. MetS was defined according to the revised NCEP ATP III criteria. Students unpaired t test was used to test differences between groups. Both logistic and linear regression analyses were performed in order to test associations between the individual MetS components and SAF.
Results: Subjects with MetS had higher SAF (2.07 ± 0.45 arbitrary units, AU) compared to individuals without MetS (1.89 ± 0.42 AU) (p < 0.001). There was a positive association between the number of MetS components and higher SAF Z‑scores (p < 0.001). Individuals in the highest SAF tertile had a higher presence of MetS (OR 2.61; 95% CI 2.48–2.75) and some of the individual components compared to subjects in the lowest SAF tertile. After correction for age, gender, creatinine clearance, HbA1c and smoking status, only elevated blood pressure and low HDL cholesterol remained significantly associated with higher SAF (p = 0.002 and p = 0.001 respectively).
Conclusion: Skin autofluorescence was associated with the presence of MetS and some of its individual compo‑nents. In addition, increasing SAF Z‑scores were observed with a higher number of MetS components. Prospective studies are needed to establish whether SAF can be used as an (additional) screening tool to predict both cardiovas‑cular disease and type 2 diabetes in high‑risk populations.
© The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
BackgroundAdvanced glycation end products (AGEs) comprise a group of largely irreversibly glycated proteins, lipids and
nucleic acids which represent chronic exposure to hyper-glycaemia and oxidative stress [1, 2]. AGEs are formed via several pathways, usually the Maillard reaction between carbonyl groups of reducing sugars and free amino groups from proteins. AGEs accumulate in the skin as a result of ageing [3, 4]. The formation and accumulation may be increased as a result of both endogenous and exogenous factors, including hyperglycaemia in diabetes,
Open Access
Diabetology &Metabolic Syndrome
*Correspondence: [email protected] 1 Department of Endocrinology, University of Groningen, University Medical Center Groningen, HPC AA31, P.O. Box 30001, 9700 RB Groningen, The NetherlandsFull list of author information is available at the end of the article
Page 2 of 12van Waateringe et al. Diabetol Metab Syndr (2017) 9:42
impaired renal excretion in subjects with kidney failure, as well as dietary intake and tobacco smoking [5–8].
Since the past decade, it has become possible to esti-mate tissue AGE accumulation non-invasively by meas-uring autofluorescence of the skin (SAF) [9]. In our previous study we showed that SAF was associated with several clinical and lifestyle parameters [10]. SAF has previously been validated against tissue AGE measure-ments and reference values against age were obtained [11, 12]. SAF was reported to be elevated in subjects with type 1 and 2 diabetes [9, 13]. Moreover, SAF has been shown to be a strong predictor of long-term cardiovas-cular complications and mortality in both type 1 and type 2 diabetes and end-stage renal failure [14–18]. In addi-tion, recent studies have shown higher SAF levels to be associated with coronary artery disease, peripheral artery disease and (sub)clinical atherosclerosis independent of diabetes [19–21].
The metabolic syndrome (MetS) is a cluster of cardio-metabolic abnormalities associated with increased risk for cardiovascular disease (CVD) and type 2 diabetes mellitus [22, 23]. The MetS is a worldwide problem which prevalence increases worldwide, particularly due to the growing epidemic of obesity [24–26]. Glycation is known to play an essential role in the mechanism that leads to the formation of AGEs [6].
It has been shown that AGEs increase inflammation and oxidative stress hereby promoting insulin resistance. On the other hand, a low AGEs diet improves insulin sensitivity [27, 28].
However, the association of the other cardiometabolic components with SAF has not been assessed in detail. As SAF measurement might be used as a future screening tool in high-risk populations, such as the MetS, to refine estimation of risk of future cardiovascular events or development of type 2 diabetes, knowledge of potential associations with SAF is important. Therefore, the aim of this cross-sectional study was to assess SAF in subjects with MetS. We examined the association between the individual MetS components and SAF in a large-scale general population.
MethodsParticipantsSubjects included were participants from the LifeLines Cohort Study [29], a large population-based cohort study in the northern region of the Netherlands exam-ining the interaction between genetic and environ-mental factors associated with chronic diseases and healthy ageing. Between 2006 and 2013, individuals from the three northern provinces of the Netherlands were invited to participate in the study. At baseline,
both physical examination and extensive question-naires were collected from more than 167,000 par-ticipants [30]. All participants have provided written informed consent before participating in the study. The study has been approved by the Medical Ethics Review Committee of the University Medical Center Gron-ingen. For the present study, we included subjects of Western European descent between 18 and 80 years of age having a SAF measurement available (n = 82,515). We excluded subjects with either missing data for MetS status (n = 1221) and those with a serum creati-nine >140 µmol/L (n = 75), as severely reduced kidney function itself increases AGE levels. Furthermore, sub-jects with missing data for diabetes status (n = 86) were excluded, as were those with type 1 diabetes (n = 177), type 2 diabetes (n = 2157) or previous gestational dia-betes (n = 128) leaving 78,671 non-diabetic individuals for analyses.
Clinical and lifestyle dataThe following clinical data were used: age, gender, body mass index (BMI), waist circumference, systolic and dias-tolic blood pressure, serum lipids, fasting plasma glucose, HbA1c, creatinine clearance, use of medication, and self-reported history of CVD (myocardial infarction and cer-ebrovascular accident). Information regarding smoking behaviour was collected by extensive questionnaires, as described earlier [10]. Pack-years of smoking were cal-culated as the number of cigarette packages smoked per day multiplied by the number of years an individual had smoked. Data regarding coffee consumption (cups of cof-fee per day) were obtained by questionnaire. We were not able to distinguish between caffeinated and decaffeinated coffee consumption.
Physical measurementsWeight was measured to the nearest 0.1 kg and height and waist circumference to the nearest 0.5 cm by trained technicians using calibrated measuring equip-ment, with participants wearing light clothing and no shoes. Waist circumference was measured with a tape around the body between the lower rib margin and the iliac crest. BMI was calculated as weight divided by height squared (kg/m2). Systolic and diastolic blood pressure were measured every minute during 10 min in the supine position using an automated Dinamap Moni-tor (GE Healthcare, Freiburg, Germany). The average of the last three readings was recorded. SAF was assessed as the mean of three consecutive measurements using the AGE Reader (DiagnOptics Technologies BV, Gron-ingen, the Netherlands) in all participants, as described previously [9–11].
Page 3 of 12van Waateringe et al. Diabetol Metab Syndr (2017) 9:42
Biochemical measuresBlood samples were taken in the fasting state between 8.00 and 10.00 a.m. and transported to the LifeLines lab-oratory facility at room temperature or at 4 °C, depend-ing on the sample requirements. On the day of collection, HbA1c (EDTA-anticoagulated) was analyzed using a NGSP-certified turbidimetric inhibition immunoas-say on a Cobas Integra 800 CTS analyzer (Roche Diag-nostics Nederland BV, Almere, the Netherlands). Serum creatinine was measured on a Roche Modular P chem-istry analyzer (Roche, Basel Switzerland), and creatinine clearance was calculated with the chronic kidney disease epidemiology collaboration (CKD-EPI) formula [31]. Total and high density lipoprotein (HDL) cholesterol were measured using an enzymatic colorimetric method, triglycerides using a colorimetric UV method, and low density lipoprotein (LDL) cholesterol using an enzy-matic method, on a Roche Modular P chemistry analyzer (Roche, Basel, Switzerland). Fasting blood glucose was measured using a hexokinase method.
Definition of the metabolic syndromeDiagnosis of MetS was established if a subject satisfied at least three out of five criteria according to the revised National Cholesterol Education Programs Adults Treat-ment Panel III (NCEP ATPIII criteria) [22]: (1) systolic blood pressure ≥130 mmHg and/or diastolic blood pres-sure ≥85 mmHg and/or use of antihypertensive medi-cation; (2) HDL cholesterol levels <1.03 mmol/L in men and <1.30 mmol/L in women and/or use of lipid-lowering medication influencing HDL levels; (3) triglyceride lev-els ≥1.70 mmol/L and/or use of triglyceride-lowering medication; (4) waist circumference ≥102 cm in men and ≥88 cm in women; (5) fasting glucose level between 5.6 and 7.0 mmol/L. As mentioned earlier, people with diabetes were excluded from analysis to reflect ‘true’ MetS.
Calculations and statistical analysesData are shown as mean ± standard deviation (SD) or median and interquartile range (IQR) in case of non-normally distributed data. Student’s unpaired t test, Analysis of Variance (ANOVA) or Chi Square test were performed to compare groups. Age-adjusted SAF levels (Z-scores) were calculated based on the total popula-tion (separated for males and females) as SAF and MetS are strongly affect by ageing [10, 32]. Next, we classi-fied individuals into tertiles of their age-adjusted SAF Z-scores, in men: lowest SAF Z ≤ −0.59, intermedi-ate SAF −0.60 < Z < 0.49 and highest SAF Z ≥ 0.50; in women: lowest SAF Z ≤ −0.72, intermediate SAF −0.73 < Z < 0.33 and highest SAF Z ≥ 0.34. Logistic regression analysis was performed to assess whether
either of the SAF groups (low SAF was set as a refer-ence) were associated with the presence of MetS and its components. Model 1 shows the unadjusted association between tertiles of SAF Z-scores and MetS as well as its individual components. In model 2, we adjusted for gen-der and BMI. In model 3, we additionally adjusted for cre-atinine clearance, HbA1c, current smoking, pack-years and CVD history. Linear regression analysis was per-formed to examine the association between each of the individual MetS components and SAF among the popu-lation with MetS. In the multivariate models, we adjusted for determinants of SAF reported in our previous study, including age, gender, BMI, creatinine clearance, HbA1c, smoking status, packyears, and CVD history [10]. SPSS (version 22, IBM, Armonk, NY, USA) was used for statis-tical analyses. A p value <0.001 (two-tailed) was consid-ered statistically significant.
ResultsClinical characteristicsTable 1 shows the clinical characteristics of the study population stratified for gender and MetS status. The overall prevalence of MetS was 19% in men and 12% in women.
In both genders, individuals with MetS were older than subjects without MetS and had a significantly higher BMI and waist circumference (all p < 0.001). Both in men and women, the prevalence of MI (3.5% in men and 1.0% in women) and CVA (1.1% in men and 1.2% in women) was higher among individuals with MetS compared to sub-jects without MetS (p < 0.001). The percentage of cur-rent smokers as well as the number of pack-years smoked (p < 0.001) were higher in the participants with MetS. In addition, both men and women with MetS reported higher consumption of coffee compared to individu-als without MetS (p < 0.001). Mean SAF levels were sig-nificantly higher among both male and female subjects with MetS compared to individuals without MetS (men: 2.07 ± 0.44 AU vs 1.94 ± 0.43 AU, p < 0.001; women: 2.07 ± 0.45 AU vs 1.86 ± 0.42 AU, p < 0.001). In subjects with MetS, mean SAF levels were not different between men and women (2.07 ± 0.44 AU vs 2.07 ± 0.45 AU, p = 0.715). However, among individuals without MetS, men had significantly higher SAF levels than women (1.94 ± 0.43 AU vs 1.86 ± 0.42 AU, p < 0.001) (data not shown). Furthermore, mean SAF was 2.33 ± 0.50 AU in subjects with a history of MI and 1.91 ± 0.43 AU in subjects without a history of MI (p < 0.001). Mean SAF was 2.22 ± 0.50 AU in subjects with a history of CVA and 1.91 ± 0.43 AU in subjects without a history of CVA (p < 0.001) (data not shown). Finally, within obese indi-viduals, subjects with MetS had a higher SAF than indi-viduals without MetS (2.11 ± 0.47 AU vs 1.94 v 0.41 AU,
Page 4 of 12van Waateringe et al. Diabetol Metab Syndr (2017) 9:42
p < 0.001). However, within the population with MetS, there was no significant difference in SAF between obese and non-obese individuals (2.07 ± 0.45 AU vs 2.06 v 0.45 AU, p = 0.46) (data not shown).
The association between SAF and the number of MetS componentsIn both men and women, we observed a gradual rise in age-adjusted SAF Z-scores with higher number of individuals MetS components. Compared to men without any MetS components, SAF Z-scores were
significantly higher among subjects with ≥1 MetS com-ponent (p < 0.001). Men with ≥2 MetS components had significantly higher SAF Z-scores compared to men hav-ing only one MetS component (p < 0.001). No signifi-cant differences in SAF Z-scores were observed between men with two vs three MetS components as well as men with four vs five MetS components. Among women, SAF Z-scores were significantly higher among those with ≥1 MetS component compared to women without any MetS components (p < 0.001). Women with three, four or five MetS components had significantly higher SAF Z-scores
Table 1 Clinical characteristics of the study population stratified by MetS status and gender
Data are presented as mean ± standard deviation, or median (interquartile range) and number (%)
AU arbitrary units, BP blood pressure, CVA cerebrovascular accident, GFR Glomerular Filtration Rate, HDL high density lipoprotein, LDL low density lipoprotein, MetS metabolic syndrome, Mi myocardial infarction, SAF skin autofluorescence, TG triglycerides
* p value <0.001a Creatinine clearance (Cockcroft-Gault formula), b Creatinine clearance (CKD EPI)
Characteristic Men (n = 32,601) Women (n = 46,070)
MetS Without MetS MetS Without MetS
n (%) 6220 (19) 26,381 (81) 5367 (12) 40,703 (88)
Age (years) 49 ± 11* 44 ± 13 50 ± 12* 44 ± 12
Body mass index (kg/m2) 29.8 ± 3.6* 25.5 ± 3.1 30.6 ± 5.1* 25.1 ± 4.1
Waist circumference (cm) 106 ± 9* 93 ± 9 100 ± 11* 85 ± 11
Systolic blood pressure (mmHg) 141 ± 14* 129 ± 14 138 ± 16* 121 ± 15
Diastolic blood pressure (mmHg) 82 ± 9* 76 ± 9 79 ± 9* 72 ± 9
Total cholesterol (mmol/L) 5.4 ± 1.1* 5.1 ± 1.0 5.4 ± 1.1* 5.0 ± 1.0
HDL cholesterol (mmol/L) 1.04 ± 0.23* 1.37 ± 0.30 1.24 ± 0.30* 1.65 ± 0.38
LDL cholesterol (mmol/L) 3.56 ± 0.93* 3.35 ± 0.89 3.57 ± 0.95* 3.05 ± 0.88
Triglycerides (mmol/L) 2.03 (1.60–2.73)* 1.04 (0.77–1.40) 1.72 (1.18–2.14)* 0.83 (0.64–1.11)
Creatinine clearance (mL/min)a 137 ± 36* 124 ± 28 125 ± 39* 111 ± 29
Creatinine clearance (mL/min)b 130 ± 18* 128 ± 16 135 ± 21 134 ± 18
Fasting plasma glucose (mmol/L) 5.45 ± 0.55* 4.98 ± 0.43 5.33 ± 0.61* 4.75 ± 0.42
HbA1c (%) 5.7 ± 0.3* 5.5 ± 0.3 5.7 ± 0.4* 5.5 ± 0.3
HbA1c (mmol/mol) 38.5 ± 3.8 36.7 ± 3.2 39.3 ± 3.9 36.5 ± 3.2
Statin use, n (%) 783 (13)* 1260 (5) 554 (10)* 1029 (3)
TG‑lowering medication, n (%) 44 (1)* 9 (0.01) 16 (0.3)* 3 (0.01)
BP‑lowering medication, n (%) 1445 (23)* 2008 (8) 1919 (36)* 3099 (8)
MI, n (%) 214 (3.5)* 289 (1.1) 56 (1.0)* 94 (0.2)
CVA, n (%) 70 (1.1)* 188 (0.7) 66 (1.2)* 203 (0.5)
Coffee consumption (cups per day) 4.7 (2.8–5.6)* 3.7 (2.8–5.6) 3.3 (1.9–4.7)* 2.8 (1.3–4.7)
Smoking status, n (%)
Non‑smokers 2117 (34)* 12,259 (47) 2203 (41)* 19,836 (49)
Ex‑smokers 2425 (39) 8271 (32) 1899 (36) 12,847 (32)
Current smokers 1629 (27) 5677 (21) 1228 (23) 7698 (19)
Pack‑years
Ex‑smokers 12.8 (6.5–21.9)* 8.2 (3.8–15.0) 7.8 (3.5–15.3)* 5.2 (2.2–10.4)
Current‑smokers 18.0 (10.7–27.0)* 12.9 (6.4–21.5) 16.9 (9.6–26.3)* 11.2 (5.4–18.8)
SAF (AU) 2.07 ± 0.44* 1.94 ± 0.43 2.07 ± 0.45* 1.86 ± 0.42
SAF Z‑score 0.21 ± 0.02* 0.04 ± 0.01 0.19 ± 0.02* −0.10 ± 0.01
Page 5 of 12van Waateringe et al. Diabetol Metab Syndr (2017) 9:42
compared to women with only one MetS component (p < 0.001). No differences in SAF Z-scores were found for women with two vs one MetS components as well as three vs two MetS components. Furthermore, women with either four or five MetS components had signifi-cantly higher SAF Z-scores than women with two MetS components or three MetS components (p < 0.001). In men, SAF Z-scores tended to be higher in those with one, two and three MetS components while in women SAF
Z-scores were higher in three, four or five MetS compo-nents compared to men (Fig. 1).
SAF and the prevalence of the individual MetS componentsFigure 2 shows the prevalence of the individual MetS components for both men and women in the total study population according to tertiles of age-adjusted SAF Z-scores. Among men, individuals in the highest SAF
Fig. 1 Age‑adjusted SAF Z‑scores increase with a higher number of MetS components. Bars reflect mean SAF Z‑scores ± standard error. Men: no MetS component (n = 8999), one MetS component (n = 10,535), two MetS components (n = 6847), three MetS components (3955), four MetS components (n = 1821), five MetS components (n = 445). Women: no MetS component (n = 17,062), one MetS component (n = 14,423), two MetS components (n = 928), three MetS components (n = 3725), four MetS components (n = 1365), five MetS components (n = 277). SAF skin autofluorescence, MetS metabolic syndrome
Page 6 of 12van Waateringe et al. Diabetol Metab Syndr (2017) 9:42
Fig. 2 Prevalence of the individual MetS components according to tertiles of age‑adjusted SAF Z‑scores. Bars show percentage of the metabolic syndrome components. Lowest, intermediate and highest group are based on tertiles of age‑adjusted SAF Z‑scores. SAF skin autofluorescence
Page 7 of 12van Waateringe et al. Diabetol Metab Syndr (2017) 9:42
groups had a higher prevalence of elevated blood pres-sure (58%) compared to subjects in the middle (52%) and lowest SAF group (54%).
We observed the same trend for enlarged waist circum-ference, impaired fasting glucose, elevated triglycerides and low HDL cholesterol (all p < 0.001).
In contrast to men, the most frequent MetS component in women was enlarged waist circumference (high SAF 48%, intermediate SAF 41% and lowest SAF 41%). There was a clear and significant trend among women within the highest SAF group, to be associated with higher prevalence of blood pressure, elevated triglycerides, lower HDL cho-lesterol levels and impaired fasting glucose (all p < 0.001).
Logistic regression analysis for the presence of MetS and it components across SAF tertilesTable 2 shows the results of the logistic regression analy-ses describing the association between SAF tertiles and the presence of MetS in the total population. Compared to the low SAF group which was set as a reference, high SAF was significantly associated with a higher pres-ence of MetS (odds ratio (OR) 2.61; 95% CI 2.48–2.75). After adjusting for age, gender, BMI, creatinine clear-ance, HbA1c, smoking status, packyears, CVD history, high SAF (OR 1.24; 95% CI 1.13–1.37) and intermediate SAF (OR 1.11; 95% CI 1.01–1.22) remained significantly associated with the presence of MetS (Table 2, model 3).
Table 2 Unadjusted and adjusted odds ratios for metabolic syndrome and its components associated with tertiles of SAF (total population)
Data are presented as odds ratios (95% confidence interval) per arbitrary unit (AU). SAF groups were based on tertiles of age-adjusted SAF Z-scores. Model 1 = unadjusted; model 2 = adjusted for age, gender, BMI; model 3 = adjusted for age, gender, BMI, HbA1c, creatinine clearance, current smoking, pack-years, MI and CVA
Significant associations are shown in italic
BMI body mass index, CVA cerebrovascular accident, HDL high density lipoprotein, MI myocardial infarction, OR odds ratio, SAF skin autofluorescence
Metabolic syndrome Model 1 Model 2 Model 3
OR p value OR p value OR p value
SAF (continuous) 2.37 (2.27−2.48) <0.0001 1.36 (1.28–1.44) <0.0001 1.17 (1.08–1.26) <0.0001
Low SAF Ref. Ref. Ref.
Intermediate SAF 1.71 (1.62–1.81) <0.0001 1.13 (1.06–1.21) <0.0001 1.11 (1.01–1.22) 0.031
High SAF 2.61 (2.48–2.75) <0.0001 1.38 (1.29–1.48) <0.0001 1.24 (1.13–1.37) <0.0001
Elevated blood pressure
SAF (continuous) 3.03 (2.92–3.14) <0.0001 1.25 (1.20–1.31) <0.0001 1.21 (1.14–1.29) <0.0001
Low SAF Ref. Ref. Ref.
Intermediate SAF 1.71 (1.65–1.77) <0.0001 1.06 (1.02–1.11) 0.005 1.04 (0.98–1.11) 0.220
High SAF 2.93 (2.82–3.03) <0.0001 1.18 (1.12–1.24) <0.0001 1.16 (1.08–1.24) <0.0001
Impaired fasting glucose
SAF (continuous) 2.59 (2.47–2.72) <0.0001 1.17 (1.10–1.25) <0.0001 1.09 (1.00–1.19) 0.049
Low SAF Ref. Ref. Ref.
Intermediate SAF 1.90 (1.78–2.03) <0.0001 1.09 (1.01–1.17) 0.026 1.08 (0.97–1.20) 0.185
High SAF 3.16 (2.97–3.37) <0.0001 1.34 (1.24–1.45) <0.0001 1.27 (1.14–1.42) <0.0001
Low HDL cholesterol
SAF (continuous) 1.08 (1.03–1.12) 0.001 1.46 (1.39–1.54) <0.0001 1.27 (1.19–1.36) <0.0001
Low SAF Ref. Ref. Ref.
Intermediate SAF 0.96 (0.92–1.01) 0.082 1.08 (1.02–1.13) 0.004 1.02 (0.94–1.10) 0.663
High SAF 1.01 (0.96–1.05) 0.786 1.27 (1.20–1.34) <0.0001 1.13 (1.04–1.22) 0.003
Elevated triglycerides
SAF (continuous) 1.78 (1.70–1.85) <0.0001 1.29 (1.22–1.37) <0.0001 1.08 (1.00–1.16) 0.029
Low SAF Ref. Ref. Ref.
Intermediate SAF 1.49 (1.41–1.57) <0.0001 1.12 (1.05–1.18) <0.0001 1.04 (0.95–1.13) 0.426
High SAF 1.89 (1.80–1.98) <0.0001 1.34 (1.25–1.42) <0.0001 1.17 (1.07–1.28) 0.001
Enlarged waist circumference
SAF (continuous) 1.89 (1.82–1.95) <0.0001 1.31 (1.23–1.39) <0.0001 1.32 (1.21–1.44) <0.0001
Low SAF Ref. Ref. Ref.
Intermediate SAF 1.45 (1.40–1.50) <0.0001 1.11 (1.05–1.18) 0.001 1.14 (1.04–1.25) 0.004
High SAF 1.93 (1.86–2.00) <0.0001 1.26 (1.18–1.35) <0.0001 1.32 (1.20–1.46) <0.0001
Page 8 of 12van Waateringe et al. Diabetol Metab Syndr (2017) 9:42
Considering the individual MetS components, high SAF (OR 3.16; 95% CI 2.97–3.37 and intermediate SAF (OR 1.90; 95% CI 1.78–2.03) were significantly associated with the presence of impaired fasting glucose, although the OR attenuated after adjusting for several covariables (Table 2, models 1, 2 and 3). We also found high SAF (OR 2.93; 95% CI 2.82–3.03) and intermediate SAF (OR 1.71; 95% CI 1.65–1.77) to be associated with the presence of elevated blood pressure (Table 2, model 1). Finally, high SAF (OR 1.93; 95% CI 1.86–2.00) and intermedi-ate SAF (OR 1.45; 95% CI 1.40–1.50) were also associ-ated with the presence of enlarged waist circumference, which remained significant after adjusting for covariables (Table 2, models 1, 2 and 3).
Associations for SAF in the metabolic syndrome populationThe univariate associations between the individual MetS components and SAF levels in the MetS population are shown in Table 3. In subjects with MetS, the impaired
fasting glucose and elevated blood pressure compo-nents gave the strongest increase in SAF. Subjects with MetS having the impaired fasting glucose component had a 0.12 AU higher SAF compared to subjects with-out this particular component. A similar association was observed for individuals with MetS having the elevated blood pressure who had a 0.11 AU higher SAF than those without elevated blood pressure. Multivariate analyses showed that after adjusting for several determinants of SAF, elevated blood pressure (0.05 AU) and low HDL cholesterol (0.04 AU) were significantly associated with higher SAF. Impaired fasting glucose, elevated triglyc-erides and enlarged waist circumference were not sig-nificantly associated with SAF. Regarding the clinical and lifestyle factors, age, HbA1c, current smoking, packyears and a history of CVD were all significantly associated with higher SAF whereas a higher creatinine clearance was associated with lower SAF.
DiscussionIn the present study, we have demonstrated that SAF lev-els were higher in both male and female participants with MetS compared to those without MetS. Furthermore, SAF was significantly and independently associated with the presence of MetS and some of its individual com-ponents, particularly elevated blood pressure, impaired fasting glucose and enlarged waist circumference.
One of the main findings of the present study was that we observed significantly higher SAF levels in subjects with MetS compared to individuals without MetS, which is in line with a study by Den Engelsen et al. [33]. These authors observed higher SAF levels in obese subjects with MetS compared to those without MetS. The latter group may be considered as “healthy obese”, which is also reflected by their SAF level. Additional analyses on our data showed a similar pattern (data not shown). In our study, 45% of men and 51% of women with MetS were obese, as defined by a BMI above 30 kg/m2. However, within the population with MetS, we did not observe a statistically significant difference in SAF between obese and non-obese individuals. Within the same population, subjects with an enlarged waist circumference had higher SAF than subjects without an enlarged waist circumfer-ence. These findings imply that not general obesity but an enlarged waist circumference, or visceral obesity has more impact on SAF within individuals with MetS.
Next, our results may not be compared directly to those from Monami et al. [34] who have also shown that SAF levels are elevated among diabetic individuals with MetS. Mean SAF was higher than in our study as their cohort primarily consisted of type 2 diabetic individuals with a mean diabetes duration of 12 years. Individuals with type 2 diabetes have in general higher SAF than subjects
Table 3 Associations for skin autofluorescence in the met-abolic syndrome population
Data are shown as coefficient B (standard error) per arbitrary unit (AU). The individual MetS components were included into the model as categorical variables (yes/no) while the other variables were continuous variables
Significant associations are shown in italic
CVA cerebrovascular accident, HDL high density lipoprotein, MI myocardial infarctiona Current smoking vs non- and former smoking
Coefficient B SE p value
Univariate model
Elevated blood pressure 0.113 0.012 <0.0001
Low HDL cholesterol −0.094 0.009 <0.001
Elevated triglycerides 0.029 0.009 0.001
Impaired fasting glucose 0.124 0.008 <0.0001
Enlarged waist circumference 0.038 0.011 0.001
Multivariate model
Elevated blood pressure 0.044 0.015 0.003
Low HDL cholesterol 0.036 0.012 0.002
Elevated triglycerides −0.001 0.011 0.920
Impaired fasting glucose 0.008 0.012 0.502
Enlarged waist circumference 0.016 0.014 0.269
Age 0.019 0.001 1.3 × 10−159
Male gender −0.016 0.011 0.272
Creatinine clearance (mL/min) 0.001 0.0002 0.014
HbA1c (%) 0.055 0.016 2.3 × 10−4
Coffee consumption (cups/day)
0.024 0.002 6.6 × 10−29
Current smokinga 0.116 0.011 1.1 × 10−23
Pack‑years 0.004 0.0003 5.6 × 10−31
MI 0.062 0.029 0.033
CVA 0.026 0.043 0.562
Page 9 of 12van Waateringe et al. Diabetol Metab Syndr (2017) 9:42
without diabetes [9]. Furthermore, subjects in their study were older and had a higher prevalence of CVD, both are associated with higher SAF [11, 14].
In addition to the observation of higher SAF levels in subjects with MetS, we also found that a higher num-ber of individual MetS components coincides with even higher SAF Z-scores. A previous study has already shown that a higher number of MetS components was associ-ated with higher serum AGEs levels [35]. Clinical studies have demonstrated that a higher number of MetS com-ponents is associated with both incident CVD and type 2 diabetes [36–38]. Klein et al. showed that individuals with one MetS components had 2.5% risk of incident CVD in the next 5 years whereas subjects with four or more MetS components had an almost 15% risk. The 5-years risk for type 2 diabetes increased from 1.1% (one MetS component) to 17.9% (≥four MetS components) [36]. An 11-year follow-up study demonstrated an almost linear relationship between the number of individual MetS components and the risk of coronary heart disease in subjects without a history of CVD or type 2 diabetes [38]. Therefore, we suggest that an increase in SAF may reflect an even higher risk of type 2 diabetes and CVD.
It has been reported that the prevalence of both MetS and its components differ between men and women [39]. In men, we observed that elevated blood pressure was the most prevalent MetS component. Moreover, we found that subjects in the highest SAF group had a higher prevalence of elevated blood pressure compared to indi-viduals in the intermediate or lowest SAF group. A few studies have described the association between SAF and elevated blood pressure, but the results are contradictory. For example, in renal transplant recipients, systolic blood pressure was positively associated with SAF [40] whereas neither systolic nor diastolic blood pressure was related to SAF in a recent Japanese study among type 2 dia-betic individuals [41]. A recent study by Botros et al. [42] showed that both systolic and diastolic blood pressure were significantly associated with SAF. They showed that individuals with elevated blood pressure had a higher odds for having a SAF level > median, compared to sub-jects without elevated blood pressure. Elevated blood pressure may well be a consequence of increased AGE accumulation. A recent study demonstrated that carotid-femoral pulse-wave velocity and central pulse pressure were independently associated with plasma AGEs [43]. Several AGEs are able to form crosslinks within collagen in the vascular wall, which may result in impaired vas-cular elasticity and increased arterial stiffness, causing blood pressure to rise [44, 45]. Our data together with previous studies suggest that AGE accumulation may indeed be involved in the underlying pathophysiology of elevated blood pressure.
In contrast to men among we found elevated blood pressure to be the most prevalent component, we observed that enlarged waist circumference was the most prevalent MetS component among women. Indi-viduals with high SAF levels had a higher presence of enlarged waist circumference compared to subjects with intermediate or low SAF levels. However, in the mul-tivariable analyses, enlarged waist circumference was not significantly associated with SAF. The correlation between waist circumference or BMI and higher SAF levels has been demonstrated among subjects with type 2 diabetes [34]. Recently, it has been shown that SAF lev-els were elevated among individuals with central obesity compared to lean subjects [33]. Interestingly, Angoorani et al. [46] have demonstrated that dietary consump-tion of AGEs is associated with MetS, and in particular abdominal obesity. Furthermore, it was observed that an increased consumption of food AGEs was associated with an even higher risk of (abdominal) obesity. They reported that individuals with a high AGEs consumption had a higher fat intake, and indeed it is known that fat contains a significant amount of dietary AGEs per gram of weight [47]. Another possible mechanism that has been reported to increase AGEs accumulation in obese individuals is oxidative stress [48, 49]. Autoxidation of lipoproteins result in the formation of advanced lipoxida-tion end products formation (ALEs) such as carboxym-ethyllysine (CML) [1].
Next, we have shown that higher SAF is significantly associated with an increased presence of impaired fast-ing glucose. After adjusting for HbA1c, impaired fast-ing glucose was not associated with SAF probably as a consequence of high collinearity. A previous study already demonstrated that among subjects with central obesity, fasting glucose levels were significantly associ-ated with higher SAF in univariate regression analy-ses but not after adjusting for covariables [33]. Another recent study reported no significant difference in plasma AGEs between women with normal fasting glucose and impaired fasting glucose [50]. As we included in our study subjects without diabetes only, and glucose levels were relatively low (<6.9 mmol/L), this may be the rea-son why fasting glucose was not associated with SAF. In individuals with diabetes, the formation of AGEs is accel-erated particularly due to (chronic) hyperglycaemia [51]. Glucose plays an essential role in the formation of AGEs as protein amino groups and lipids are non-enzymatically glycated to form stable structures on long-lived tissues [4, 52]. A second pathway which leads to the formation of AGEs is through autoxidation of glucose by reactive oxygen species and through formation of carbonyl com-pounds [1]. It has been shown that AGEs are involved in beta-cell injury, probably caused by inflammation and
Page 10 of 12van Waateringe et al. Diabetol Metab Syndr (2017) 9:42
oxidative stress thought the AGE–RAGE interaction [53]. This may be prevented by consumption of a low-AGE diet, which has been suggested to improve insulin sensi-tivity [54, 55].
After adjusting for several determinants, having a low HDL cholesterol was significantly associated with higher SAF levels but elevated triglycerides was not. Among individuals with MetS, HDL was just above the limit in men and slightly decreased in women, while statin use was 13% in men and 10% in women. Additional analysis showed that statin users had significantly higher SAF Z scores than those not using statins, also after correcting for age. Triglycerides were slightly elevated in women, but higher in men. Around 1% of individuals with MetS used triglycerides lowering medication. There was no significant difference in SAF Z scores between subject using triglycerides lowering medication and subjects not using this kind of medication. Limited data exist on the association between SAF and both HDL cholesterol and triglycerides. In subjects with type 2 diabetes, HDL cholesterol levels were negatively, and triglycerides were positively associated with SAF [14, 34]. Similar associa-tions have been reported between serum AGEs levels and triglycerides and HDL cholesterol levels in diabetes [56]. In addition, higher consumption of AGE-rich foods was associated with hypertriglyceridemia [46]. HDL choles-terol has been reported to inhibit oxidative modification of LDL cholesterol [57]. A study in 200 type 2 diabetic subjects showed that higher anti-oxidative capacity of HDL was associated with lower SAF but not plasma HDL cholesterol levels itself [58]. Circulating AGEs may impair the capacity of HDL to protect against oxidation of LDL cholesterol which potentially increases oxida-tive stress. In turn this might accelerate the formation of AGEs [59] and plays a role in atherosclerosis [60].
The strength of this study is its large and well-char-acterized study population, including high quality data on anthropometric and clinical measurements. This resulted in a good statistical power and the ability to perform stratified analysis. Moreover, this is the largest study in subjects without diabetes and impaired renal failure showing the association between SAF and several cardiometabolic risk factors. A limitation of the study includes the cross-sectional design, which does not allow us to draw any conclusions about causality in the associa-tion between SAF levels and the risk of cardiometabolic diseases.
ConclusionThe present findings of elevated SAF levels in subjects with MetS, the positive association between the num-ber of individual MetS components and higher SAF lev-els, as well as the observation that higher SAF levels are
associated with higher prevalence of the individual com-ponents, provide further evidence that accumulation of AGEs may contribute to the pathophysiology of sev-eral cardiometabolic risk factors. Prospective studies are needed to demonstrate whether SAF measurement can be used as an additional non-invasive screening tool to detect individuals at high-risk for both CVD and incident type 2 diabetes.
AbbreviationsAGEs: advanced glycation end products; AU: arbitrary units; BMI: body mass index; CVD: cardiovascular disease; HDL: high density lipoprotein; MetS: meta‑bolic syndrome; SAF: skin autofluorescence.
Authors’ contributionsBHRW was the primary investigator. RPW and BHRW contributed to the study design. RPW performed the statistical analyses. RPW, BHRW, MMvdK, HLL, JVO, RG, SNS and ADP contributed to interpretation of the data and analyses. RPW drafted the manuscript. All authors read and approved the final manuscript.
Author details1 Department of Endocrinology, University of Groningen, University Medical Center Groningen, HPC AA31, P.O. Box 30001, 9700 RB Groningen, The Nether‑lands. 2 Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada. 3 Department of Internal Medicine, Medical Center Leeuwarden, 8934 AD Leeuwarden, The Netherlands.
AcknowledgementsThe authors wish to acknowledge all participants of the LifeLines Cohort Study and everybody involved in the set‑up and implementation of the study.
Competing interestsRG is founder and shareholder of DiagnOptics BV, Groningen, the Netherlands, manufacturer of the AGE Reader (http://www.diagnoptics.com) which has been used in the present study. All authors declare that they have no compet‑ing interest.
Availability of data and materialsThe manuscript is based on data from the LifeLines Cohort Study. LifeLines adheres to standards for data availability. The data catalogue of LifeLines is publicly accessible on http://www.lifelines.net. All international researchers can apply for data at the LifeLines research office ([email protected]). The LifeLines system allows access for reproducibility of the study results.
Ethics approval and consent to participateThe study was approved by the Medical Ethical Committee of the University Medical Center Groningen. Informed consent was obtained from all individual participants included in the Lifelines study.
FundingLifelines has been funded by a number of public sources, notably the Dutch Government, The Netherlands Organization of Scientific Research NOW [Grant 175.010.2007.006], the Northern Netherlands Collaboration of Provinces (SNN), the European fund for regional development, Dutch Ministry of Economy Affairs, Pieken in de Delta, Provinces of Groningen and Drenthe, the Target project, BBMRI‑NL, the University of Groningen, and the University Medical Center Groningen, The Netherlands. This work was supported by the National Consortium for Healthy Ageing, and funds from the European Union’s Seventh Framework program (FP7/2007–2013) through the BioSHaRE‑EU (Biobank Standardisation and Harmonisation for Research Excellence in the European Union) project, grant agreement 261433. LifeLines (BRIF4568) is engaged in a Bioresource research impact factor (BRIF) policy pilot study, details of which can be found at: https://www.bioshare.eu/content/bioresource‑impact‑factor.
Prior presentationsParts of this study were presented in abstract form at the European Congress of Endocrinology (ECE), May 2016, Munich (Germany).
Page 11 of 12van Waateringe et al. Diabetol Metab Syndr (2017) 9:42
Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims in pub‑lished maps and institutional affiliations.
Received: 13 January 2017 Accepted: 23 May 2017
References 1. Baynes JW, Thorpe SR. Glycoxidation and lipoxidation in atherogenesis.
Free Radic Biol Med. 2000;28(12):1708–16. 2. Monnier VM. Nonenzymatic glycosylation, the maillard reaction and the
aging process. J Gerontol. 1990;45(4):B105–11. 3. Dunn JA, McCance DR, Thorpe SR, Lyons TJ, Baynes JW. Age‑dependent
accumulation of N. epsilon.‑(carboxymethyl)lysine and N. epsilon.‑(carboxymethyl)hydroxylysine in human skin collagen. Biochemistry. 1991;30(5):1205–10.
4. Dyer DG, Dunn JA, Thorpe SR, Bailie KE, Lyons TJ, McCance DR, et al. Accumulation of maillard reaction products in skin collagen in diabetes and aging. J Clin Investig. 1993;91(6):2463–9.
5. Noordzij MJ, Lefrandt JD, Smit AJ. Advanced glycation end products in renal failure: an overview. J Ren Care. 2008;34(4):207–12.
6. Brownlee M. Lilly lecture 1993. Glycation and diabetic complications. Diabetes. 1994;43(6):836–41.
7. Goldberg T, Cai W, Peppa M, Dardaine V, Baliga BS, Uribarri J, et al. Advanced glycoxidation end products in commonly consumed foods. J Am Diet Assoc. 2004;104(8):1287–91.
8. Cerami C, Founds H, Nicholl I, Mitsuhashi T, Giordano D, Vanpatten S, et al. Tobacco smoke is a source of toxic reactive glycation products. Proc Natl Acad Sci USA. 1997;94(25):13915–20.
9. Meerwaldt R, Graaff R, Oomen PH, Links TP, Jager JJ, Alderson NL, et al. Simple non‑invasive assessment of advanced glycation endproduct accumulation. Diabetologia. 2004;47(7):1324–30.
10. van Waateringe RP, Slagter SN, van der Klauw MM, van Vliet‑Ostaptchouk JV, Graaff R, Paterson AD, et al. Lifestyle and clinical determinants of skin autofluorescence in a population‑based cohort study. Eur J Clin Investig. 2016;46(5):481–90.
11. Koetsier M, Lutgers HL, de Jonge C, Links TP, Smit AJ, Graaff R. Ref‑erence values of skin autofluorescence. Diabetes Technol Ther. 2010;12(5):399–403.
12. Meerwaldt R, Links T, Graaff R, Thorpe SR, Baynes JW, Hartog J, et al. Sim‑ple noninvasive measurement of skin autofluorescence. Ann N Y Acad Sci. 2005;1043:290–8.
13. van der Heyden JC, Birnie E, Mul D, Bovenberg S, Veeze HJ, Aanstoot HJ. Increased skin autofluorescence of children and adolescents with type 1 diabetes despite a well‑controlled HbA1c: results from a cohort study. BMC Endocr Disord. 2016;16(1):49.
14. Lutgers HL, Graaff R, Links TP, Ubink‑Veltmaat LJ, Bilo HJ, Gans RO, et al. Skin autofluorescence as a noninvasive marker of vascular damage in patients with type 2 diabetes. Diabetes Care. 2006;29(12):2654–9.
15. Meerwaldt R, Lutgers HL, Links TP, Graaff R, Baynes JW, Gans RO, et al. Skin autofluorescence is a strong predictor of cardiac mortality in diabetes. Diabetes Care. 2007;30(1):107–12.
16. Meerwaldt R, Hartog JW, Graaff R, Huisman RJ, Links TP, den Hollander NC, et al. Skin autofluorescence, a measure of cumulative metabolic stress and advanced glycation end products, predicts mortality in hemodialysis patients. J Am Soc Nephrol. 2005;16(12):3687–93.
17. Kimura H, Tanaka K, Kanno M, Watanabe K, Hayashi Y, Asahi K, et al. Skin autofluorescence predicts cardiovascular mortality in patients on chronic hemodialysis. Ther Apher Dial. 2014;18(5):461–7.
18. Velayoudom‑Cephise FL, Rajaobelina K, Helmer C, Nov S, Pupier E, Blanco L, et al. Skin autofluorescence predicts cardio‑renal outcome in type 1 diabetes: a longitudinal study. Cardiovasc Diabetol. 2016;15(1):127.
19. Mulder DJ, van Haelst PL, Gross S, de Leeuw K, Bijzet J, Graaff R, et al. Skin autofluorescence is elevated in patients with stable coronary artery disease and is associated with serum levels of neopterin and the soluble receptor for advanced glycation end products. Atherosclerosis. 2008;197(1):217–23.
20. de Vos LC, Noordzij MJ, Mulder DJ, Smit AJ, Lutgers HL, Dullaart RP, et al. Skin autofluorescence as a measure of advanced glycation end products deposition is elevated in peripheral artery disease. Arterioscler Thromb Vasc Biol. 2013;33(1):131–8.
21. den Dekker MA, Zwiers M, van den Heuvel ER, de Vos LC, Smit AJ, Zeebregts CJ, et al. Skin autofluorescence, a non‑invasive marker for AGE accumulation, is associated with the degree of atherosclerosis. PLoS ONE. 2013;8(12):e83084.
22. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome: an ameri‑can heart association/national heart, lung, and blood institute scientific statement. Circulation. 2005;112(17):2735–52.
23. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365(9468):1415–28.
24. van Vliet‑Ostaptchouk JV, Nuotio ML, Slagter SN, Doiron D, Fischer K, Foco L, et al. The prevalence of metabolic syndrome and metabolically healthy obesity in Europe: a collaborative analysis of ten large cohort studies. BMC Endocr Disord. 2014;14:9.
25. Cameron AJ, Shaw JE, Zimmet PZ. The metabolic syndrome: Prevalence in worldwide populations. Endocrinol Metab Clin N Am. 2004;33(2):351–75.
26. Yang L, Colditz GA. Prevalence of overweight and obesity in the united states, 2007–2012. JAMA Intern Med. 2015;175(8):1412–3.
27. de Courten B, de Courten MP, Soldatos G, Dougherty SL, Straznicky N, Schlaich M, et al. Diet low in advanced glycation end products increases insulin sensitivity in healthy overweight individuals: a double‑blind, randomized, crossover trial. Am J Clin Nutr. 2016;103(6):1426–33.
28. Ottum MS, Mistry AM. Advanced glycation end‑products: modifiable environmental factors profoundly mediate insulin resistance. J Clin Biochem Nutr. 2015;57(1):1–12.
29. Stolk RP, Rosmalen JG, Postma DS, de Boer RA, Navis G, Slaets JP, et al. Uni‑versal risk factors for multifactorial diseases: LifeLines: A three‑generation population‑based study. Eur J Epidemiol. 2008;23(1):67–74.
30. Scholtens S, Smidt N, Swertz MA, Bakker SJ, Dotinga A, Vonk JM, et al. Cohort profile: LifeLines, a three‑generation cohort study and biobank. Int J Epidemiol. 2015;44(4):1172–80.
31. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–12.
32. Hildrum B, Mykletun A, Hole T, Midthjell K, Dahl AA. Age‑specific preva‑lence of the metabolic syndrome defined by the international diabetes federation and the national cholesterol education program: the norwe‑gian HUNT 2 study. BMC Public Health. 2007;7:220.
33. den Engelsen C, van den Donk M, Gorter KJ, Salome PL, Rutten GE. Advanced glycation end products measured by skin autofluores‑cence in a population with central obesity. Dermatoendocrinology. 2012;4(1):33–8.
34. Monami M, Lamanna C, Gori F, Bartalucci F, Marchionni N, Mannucci E. Skin autofluorescence in type 2 diabetes: beyond blood glucose. Diabe‑tes Res Clin Pract. 2008;79(1):56–60.
35. Uribarri J, Cai W, Woodward M, Tripp E, Goldberg L, Pyzik R, et al. Elevated serum advanced glycation endproducts in obese indicate risk for the metabolic syndrome: A link between healthy and unhealthy obesity?. J Clin Endocrinol Metab. 2015; jc20143925.
36. Klein BE, Klein R, Lee KE. Components of the metabolic syndrome and risk of cardiovascular disease and diabetes in beaver dam. Diabetes Care. 2002;25(10):1790–4.
37. Marott SC, Nordestgaard BG, Tybjaerg‑Hansen A, Benn M. Components of the metabolic syndrome and risk of type 2 diabetes. J Clin Endocrinol Metab. 2016; jc20153777.
38. McNeill AM, Rosamond WD, Girman CJ, Golden SH, Schmidt MI, East HE, et al. The metabolic syndrome and 11‑year risk of incident cardiovascular disease in the atherosclerosis risk in communities study. Diabetes Care. 2005;28(2):385–90.
39. Kuk JL, Ardern CI. Age and sex differences in the clustering of meta‑bolic syndrome factors: association with mortality risk. Diabetes Care. 2010;33(11):2457–61.
40. Hartog JW, de Vries AP, Bakker SJ, Graaff R, van Son WJ, van der Heide JJ, et al. Risk factors for chronic transplant dysfunction and cardiovascular disease are related to accumulation of advanced glycation end‑products in renal transplant recipients. Nephrol Dial Transplant. 2006;21(8):2263–9.
Page 12 of 12van Waateringe et al. Diabetol Metab Syndr (2017) 9:42
• We accept pre-submission inquiries
• Our selector tool helps you to find the most relevant journal
• We provide round the clock customer support
• Convenient online submission
• Thorough peer review
• Inclusion in PubMed and all major indexing services
• Maximum visibility for your research
Submit your manuscript atwww.biomedcentral.com/submit
Submit your next manuscript to BioMed Central and we will help you at every step:
41. Tanaka K, Tani Y, Asai J, Nemoto F, Kusano Y, Suzuki H, et al. Skin autofluo‑rescence is associated with severity of vascular complications in japanese patients with type 2 diabetes. Diabet Med. 2012;29(4):492–500.
42. Botros N, Sluik D, van Waateringe RP, de Vries JH, Geelen A, Feskens EJ. Advanced glycation end‑products (AGEs) and associations with cardio‑metabolic, lifestyle and dietary factors in a general population: the NQplus study. Diabetes Metab Res Rev. 2017;17:259.
43. van Eupen MG, Schram MT, van Sloten TT, Scheijen J, Sep SJ, van der Kallen CJ, et al. Skin autofluorescence and pentosidine are associ‑ated with aortic stiffening: the maastricht study. Hypertension. 2016;68(4):956–63.
44. Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circula‑tion. 2006;114(6):597–605.
45. Aronson D. Cross‑linking of glycated collagen in the pathogenesis of arterial and myocardial stiffening of aging and diabetes. J Hypertens. 2003;21(1):3–12.
46. Angoorani P, Ejtahed HS, Mirmiran P, Mirzaei S, Azizi F. Dietary consump‑tion of advanced glycation end products and risk of metabolic syndrome. Int J Food Sci Nutr. 2016;67(2):170–6.
47. Uribarri J, Woodruff S, Goodman S, Cai W, Chen X, Pyzik R, et al. Advanced glycation end products in foods and a practical guide to their reduction in the diet. J Am Diet Assoc. 2010;110(6):911–916.e12.
48. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Investig. 2004;114(12):1752–61.
49. Gaens KH, Stehouwer CD, Schalkwijk CG. Advanced glycation endprod‑ucts and its receptor for advanced glycation endproducts in obesity. Curr Opin Lipidol. 2013;24(1):4–11.
50. Teichert T, Hellwig A, Pessler A, Hellwig M, Vossoughi M, Sugiri D, et al. Association between advanced glycation end products and
impaired fasting glucose: results from the SALIA study. PLoS ONE. 2015;10(5):e0128293.
51. Brownlee M, Cerami A, Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med. 1988;318(20):1315–21.
52. Brownlee M. Advanced protein glycosylation in diabetes and aging. Annu Rev Med. 1995;46:223–34.
53. Vlassara HSG. The role of advanced glycation end‑products in the etiol‑ogy of insulin resistance and diabetes. US Endocrinol. 2010;6(6):14–9.
54. Mark AB, Poulsen MW, Andersen S, Andersen JM, Bak MJ, Ritz C, et al. Consumption of a diet low in advanced glycation end products for 4 weeks improves insulin sensitivity in overweight women. Diabetes Care. 2014;37(1):88–95.
55. Uribarri J, Cai W, Ramdas M, Goodman S, Pyzik R, Chen X, et al. Restric‑tion of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of AGER1 and SIRT1. Diabetes Care. 2011;34(7):1610–6.
56. Chang JB, Chu NF, Syu JT, Hsieh AT, Hung YR. Advanced glycation end products (AGEs) in relation to atherosclerotic lipid profiles in middle‑aged and elderly diabetic patients. Lipids Health Dis. 2011;10:228.
57. Soran H, Schofield JD, Liu Y, Durrington PN. How HDL protects LDL against atherogenic modification: paraoxonase 1 and other dramatis personae. Curr Opin Lipidol. 2015;26(4):247–56.
58. Mulder DJ, de Boer JF, Graaff R, de Vries R, Annema W, Lefrandt JD, et al. Skin autofluorescence is inversely related to HDL anti‑oxidative capacity in type 2 diabetes mellitus. Atherosclerosis. 2011;218(1):102–6.
59. Zhou H, Tan KC, Shiu SW, Wong Y. Increased serum advanced glycation end products are associated with impairment in HDL antioxidative capac‑ity in diabetic nephropathy. Nephrol Dial Transplant. 2008;23(3):927–33.
60. Stocker R, Keaney JF Jr. Role of oxidative modifications in atherosclerosis. Physiol Rev. 2004;84(4):1381–478.
Therapeutic interventions against accumulation of Advanced Glycation End products (AGEs)
AbstractAdvanced Glycation End products (AGEs) are formed in a non-enzymatic reaction between reducing sugars and proteins, lipids or nucleic acids. AGEs build up in the body naturally during aging and are involved in the development of several pa-thologies such as diabetic complications, atherosclerosis and cardiovascular disease. Since AGE levels are a good predictor of diabetic complications and cardiovascular mortality, AGE measurements can provide new information to the current prognosis and treatment options of diabetic patients. Moreover, research regarding interventions to reduce AGE accu-mulation has been of major interest the latest years. This review examines interventions that have been studied in clinical trials or in in vivo studies when that compound is currently available for human use as well. Interventions can be aimed at different levels in the AGE formation pathway and depend on different mechanisms, among which antioxidant ability, scavenging of reactive carbonyl species (RCS) or breaking AGE-induced crosslinks. Pharmaceutical options show promi-sing results, yet their clinical relevance is doubtful so far due to safety concerns. For individuals with high AGE levels but no clinical symptoms, lifestyle interventions such as a low AGE diet and physical exercise might be more effective. Nutra-ceuticals, derived from food sources and available as dietary supplements, have mostly been investigated in pre-clinical studies and showed positive effects on diabetic complications such as nephro- and retinopathy. Due to the deleterious effects of AGEs on diabetes and its complications, AGE-inhibitors are interesting agents to investigate more extensively.
Keywordsadvanced glycation end products (AGEs), diabetic complications, therapy, lifestyle interventions
Introduction on Advanced Glycation End productsAdvanced glycation end products (AGEs) are a diverse set of compounds that accumulate in tissues during normal ageing and contribute to a range of diseases such as diabetes mellitus and its complications, neurodegeneration and inflammation.1 AGEs are generated when sugars react with proteins, lipids or nucleic acids in a non-enzymatic way. This glycation process is described as the Maillard reaction and is known for the browning of foods. This reaction is characterised by a few steps with intermediate products to eventually form AGEs. When the carbonyl group of reducing sugars react with the amino-terminal group of proteins, an unstable Schiff base is formed in a reversible process. During rearrangements, the more stable Amadori product is produced, e.g. the glycated haemoglobin HbA1c. When further reactions as rearrangements, oxidation and dehydration take place, AGEs will be produced.2 During these rearrangements highly reactive intermediate α-dicarbonyls, also known as reactive carbonyl species (RCS), accumulate and cause carbonyl stress. Examples of these products are 3-deoxyglucosone (3-DG) and methylglyoxal (MGO).3 RCS and AGE formation can also occur by glycoxidation or lipid peroxidation.4 Under physiological circumstances, the endogenous AGE production will take weeks or years and long-lived proteins such as collagen are the major target. Under stress conditions such as hyperglycemia or oxidative stress this reaction accelerates and can also affect short-lived substrates (e.g. enzymes and
hormones), inducing structural changes.5 AGEs can also come from exogenous sources such as food of which 10% is estimated to be absorbed in the gut.6 Animal-derived foods, high in fat and protein, consist of high AGE levels. In contrast, food that is enriched with carbohydrates, such as whole grains, vegetables and fruit, are generally low in AGEs. Since high temperatures can accelerate AGE formation, food processing by heating can contribute to the accumulation of AGEs in the body.7 Furthermore, smoking is an important exogenous source of AGEs.8
Role of AGEs in health and diseaseThe formation of AGEs and accumulation in the body are natural processes during ageing. Aging is explained as a multifactorial process leading to a gradual decline in physiological functions, affecting all tissues in the body.9 High rates of AGE accumulation in the skin have been shown to correlate with aging10 and excessive AGE accumulation can accelerate the aging process. The amount of AGEs is based on the rate of formation, determined by ROS and reducing sugars, and the rate of clearance, determined by the activity of the glyoxalase system, where glyoxalase I (Glo I) is able to detoxify reactive carbonyl compounds.11 Aging can cause an imbalance in this system, since ROS is present in a larger extent while Glo I activity is decreased.1 Furthermore, AGE accumulation is aggravated in some chronic diseases as well, such as cardiovascular disease, diabetes mellitus, renal failure and Alzheimers disease.2 AGEs
Marloes M. Roorda University of Groningen
can damage cells and tissues through several mechanisms and thereby contribute to aging or disease. First, AGEs can bind to certain receptors (RAGE; receptor for Advanced Glycation End products) on different cells. This induces several signalling cascades, among which activation of MAP kinases and the JAK/STAT pathway.14,15 Many of these signalling pathways lead to the activation of transcription factors such as NFκB, which induces a diverse set of target genes. Pro-inflammatory genes (e.g. TNF-α, IL-1 and IL-6), adhesion molecules (e.g. VCAM-1) and vasoconstrictors are activated.1,14 In addition, reactive oxygen species (ROS) are generated by activation of NADPH oxidases and then stimulate the further formation of AGEs.15 Oxidative stress and inflammation can in their turn elicit tissue damage and lead to accelerated aging.9 Besides a receptor-mediated response, AGEs are responsible for alterations in protein function. Glycation of (intracellular) proteins can alter their structure and lead to impaired function of growth factors, enzymes and transcription factors, contributing to impaired cell function.5 Furthermore, AGEs stimulate the formation of crosslinks between (intracellular) proteins, and can trap (lipo)proteins.12 Accumulation of AGEs in the extracellular matrix (ECM) can result in crosslinking
of collagen molecules leading to stiffness and decreased elasticity of tissues.16 Particularly tissues rich in ECM and long-lived proteins such as skin, skeletal muscles, tendons, heart and lens are targeted by this stiffening and is associated with aging.17 Under pathological conditions the consequences of crosslinking by AGEs include thickening of the capillary basement membrane, rigid vessels and development of atherosclerosis and glomerular sclerosis.18 In patients suffering from diabetes or renal disease, AGEs accumulate more rapidly due to hyperglycaemia, oxidative stress or impaired renal clearance. AGEs then contribute to the progression of these diseases and complications such as diabetic neuropathy, nephropathy and the formation of cataract. Atherosclerosis is the major cause of death in diabetic patients19 and is characterized by cross-linking of extracellular matrix proteins in the vessel wall by AGE accumulation, thereby trapping plasma proteins.20 Moreover, AGEs in the vessel wall interfere with the nitric oxide (NO)-mediated relaxation ability of the endothelium.21 NF-κB signalling and ROS induce apoptosis of pericytes and endothelial cells,22 contributing to diabetic retinopathy. This is enhanced by hyperpermeability of capillaries, resulting in vascular leakage.23 In addition, the thickening of the capillary basement membranes by increased synthesis of collagen and
Fig 1. During the traditional Maillard reaction reducing sugars react with the amino group of proteins to form intermediate products Schiff bases and Amadori products and eventually AGEs. More recently it appeared AGEs can be formed through other pathways such as glycoxidation and lipid peroxidation where reactive carbonyl species (RCS) are generated that covalently bind to proteins. (CML- carboxy-methyl-lysine; CEL- carboxy-et-hyl-lysine; GO: glyoxal; MGO- methylglyoxal; 3-DG- 3-deoxyglucosone)
other matrix molecules is a mechanism by which retinopathy is strengthened. 24 The same mechanisms play a role in the pathophysiology of diabetic nephropathy. Apoptosis of mesangial cells25 and the thickening of the glomerular basement membrane is partly responsible for altered filtration, albuminuria and eventually renal failure.2
AGE accumulation represents ‘glycaemic memory’: the phenomenon that explains the sustained beneficial effects long after a period of intensive glycaemic control, as well as the prolonged harmful effects after hyperglycaemia.26,27 Together with their role in diabetic complications, measuring
AGEs is emerging as a tool to predict the odds of developing complications and detect patients at risk. The AGE Reader (Diagnoptics, Groningen, the Netherlands) provides a non-invasive, quick and reproducible way for the AGE-related skin autofluorescence (SAF). Skin AGE levels proved to be an independent predictor of microvascular complications in type 2 diabetes.28 Furthermore, skin autofluorescence is, except for age, the best predictor for (cardiovascular) mortality and provides additional information to conventional CV risk assessment engines.29
Fig. 2 AGEs contribute to aging and disease by different mechanisms. Glycation of proteins alters their structure and function, leading to impaired cell function. AGE-RAGE interaction activates NFkB, inducing several cellular responses, such as apoptosis, production of pro-inflammatory cytokines and ROS. Finally, AGEs form crosslinks between collagen and other proteins, leading to tissue stiffening. These are key processes in many diabetic complications, such as atherosclerosis, diabetic nephropathy and diabetic neuropathy.
Interventions to reduce AGEsSince AGEs have shown to play an important role in aging and the development and progression of many chronic diseases, they are an excellent target for new therapies. To diminish the harmful effect of AGEs on cellular and tissue functioning, interventions are proposed that either avoid the further formation or accumulation of AGEs or remove the AGEs that are already formed. This review gives an overview of existing and potential interventions that can inhibit AGEs now or in the near future, which are classified in pharmacologic, lifestyle and nutraceutical interventions.
Pharmacologic interventionsResearchers have been ambitious to find substances with AGE-reducing properties. Compounds that have been studied extensively are Aminoguanidine (AG) and Alagebrium (ALT-
711). Aminoguanidine (AG) is a small molecule that reacts with dicarbonyl compounds (e.g. MG and 3-DG) and Amadori intermediates to inhibit the formation of AGEs.30 The first clinical trial (ACTION) was performed to evaluate the effect of AG on the further development of diabetic nephropathy. A large cohort of 690 patients with T1DM and known nephro- and retinopathy participated and were treated for 2-4 years with AG. Overall, a significant reduction of diabetes complications was observed. AG administration reduced the 24-hour proteinuria and could prevent the decrease in glomerular filtration rate. However, the inhibition of AGE formation by AG showed no effect on serum creatinine.31 A second trial, involving AG therapy in T2DM patients, was early terminated due to undesirable side effects such as abnormalities in liver
function, gastrointestinal problems and anemia.32 Alagebrium (ALT-711) has the ability to break crosslinks of Maillard reaction products and demonstrated positive effects on atherosclerosis and diabetic nephropathy in vivo. Clinical studies that have been performed mostly investigated the use of Alagebrium in patients with hypertension or heart failure. Two studies that examined hypertensive patients treated with Alagebrium for a relative short period (8-10 weeks)33,34, showed some beneficial effects on several cardiovascular variables, such as an increase in arterial compliance and a decrease of arterial pulse pressure.33 Furthermore endothelial function was improved and the therapy might reduce arterial remodelling. Nevertheless, the same study reported no changes in cardiac output, blood pressure and systolic or diastolic function and other cardiovascular variables.34 In a study where 23 patients with diastolic heart failure were treated for four months ambiguous results were found. Although diastolic function and left ventricular mass were improved, no change in VO2 max, blood pressure or aortic distensibility were found.35 Another study observing 102 heart failure patients after 9 months of treatment did not show positive results and could not find an improvement of diastolic and systolic function, AGE accumulation or New York Heart Association (NYHA) classification.36 Similarly, no convincing results on hemodynamics or exercise capacity could be detected after 1 year of treatment in healthy individuals.37,38
Due to the mentioned safety and efficacy problems, it is implausible that Aminoguanidine and Alagebrium will be used for the treatment or prevention of diabetic complications. Azeliragon is a RAGE inhibitor and has been tested in clinical trials to diminish Alzheimers Disease (AD). RAGE is not only a receptor for AGEs, but can bind amyloid β as well. In AD, RAGE expression is upregulated in the brain and contributes to inflammation, oxidative stress and neurodegeneration.39 RAGE antagonist Azeliragon (also known as TTP488 or PF-04494700) was administered to 399 patients for 18 months to inhibit the interaction between RAGE and amyloid β and block signal transduction.40 This also might be interesting to counteract the detrimental effects of AGEs through its receptor. A low dose was suggested to have a decreased decline on the Alzheimer’s Disease Assessment Scale–cognitive (ADAS-cog), a test that determines parameters as memory, reasoning, language and orientation.41 Nevertheless, there was no significant difference in other clinical markers and the study was terminated early.40 The drug was developed earlier for diabetic neuropathy but this study was discontinued as well. Besides pharmaceuticals that specifically target AGEs, there is another subset of generic drugs, initially developed to decrease blood pressure or cholesterol, but happen to have an effect on AGEs as well. Several small studies on metformin, glucose-lowering medication, showed some beneficial effects on glycation measures, such as a decrease of MG42 and lower AGEs and oxidative stress in patients with type 2 diabetes.43 Not all studies were able to find additional effects, therefore the AGE-inhibition capacity of metformin might be attributed merely to improved glycaemic control instead of dicarbonyl quenching. Lipid-lowering medication might inhibit AGE formation as well due to anti-oxidative properties, which partly reduces
lipid peroxidation. Atorvastatin showed a decrease in serum AGEs in non-alcoholic steatohepatitis (NASH) patients with dyslipidemia after 12 months of treatment.44 Serum AGEs were also reduced in patients with non-diabetic chronic kidney disease and dyslipidemia after one year of atorvastatin treatment.45 This effect was also observed in diabetic patients that received cerivastatin for three months.46 In addition to the decrease in serum AGEs, simvastatin showed a decrease of RAGE expression in carotid artery plaques, by inhibition of AGE formation.47 Finally, blood pressure-regulating medication also has a potential effect on AGEs. Until now, only one small study on ACE-inhibitors has evaluated the effect on AGE formation. Ramipril treatment for two months decreased fluorescent AGEs, but not non-fluorescent CML, alongside reduced blood pressure and proteinuria.48
Furthermore, Angiotensin Receptor blockers have shown in several small studies that they possess AGE-reducing effects. One year of valsartan treatment decreased serum AGEs, but did not affect other metabolic and oxidative markers in diabetic hypertensive patients.49 Candesartan administration to diabetic patients for three months decreased urinary AGEs50 and in addition slightly improved creatinine clearance in diabetic kidney disease patients.51 In contrast, a larger randomised controlled trial with a longer follow-up period could not detect a treatment effect of irbestartan on AGEs in type 2 diabetic subjects with microalbuminuria.52
Lifestyle interventions Pharmaceutic interventions against AGEs are not approved yet to be clinically used. For individuals that have high AGE levels but no clinical signs of disease yet, non-medical interventions such as adopting a healthy lifestyle might be a more effective approach to prevent further AGE accumulation and increase healthspan (i.e. the disease-free time of life).
Low AGE dietSince the composition and especially the preparation of food largely determine the amount of exogenous AGE intake, a diet low in AGEs can reduce the absorbed AGEs from the gut. Several studies on a low AGE diet have been completed, using different study populations (healthy and obese subjects as well as patients with diabetes and renal failure). The duration of the low AGE differed between studies, but were all between 1 and 4 months. The decrease of AGEs in the diet was between 30 and 60%, which was generally due to differences in cooking methods. In all studies an isocaloric, low AGE diet showed a decrease in serum AGEs and in most studies, except for one53, this decrease is accompanied by a reduction in markers of inflammation and oxidative stress.54–59 In diabetic and obese subjects with insulin resistance, the HOMA-determined insulin sensitivity improved.60,61 A calorie-restricted diet reduced plasma AGEs as well, which can be due to a reduced intake of food AGEs or because of other mechanisms such as upregulation of sRAGE or decreased ROS formation.62 It must be noted that AGE intake can largely differ in different populations and countries due to differences in the preparation of food. The effects of a low AGE diet should not be undermined since the contribution of dietary AGEs is larger than the endogenously amount of formed AGEs in plasma.63
Physical exercisePhysical exercise has shown to be protective against cardiovascular disease, increases longevity and is an important tool to prevent the development of diabetes in subjects with impaired glucose tolerance.64. The influence of exercise on AGE levels has been described in several studies. The first study investigated the effect of short and long runs on changes in methylglyoxal (MG) content in red blood cells of trained and untrained students. Long runs showed to have the largest reduction in MG concentration; 41% and 60% in untrained and trained students respectively. 65 Another study explored the influence of life-long endurance running on the accumulation of AGEs in connective tissue and found that life-long runners had a 21% lower AGE crosslink density of pentosidine in patellar tendons, accompanied by an 11% decrease in skin AGE levels.66 Doing Tai Chi, an exercise of moderate intensity and an aerobic nature, for twelve months, showed a decrease in serum AGEs, most likely by stimulating antioxidant enzymes that reduce oxidative stress.67 In addition, a study involving middle-aged females in a 12-week lifestyle modification demonstrated a decrease in serum AGEs, as well as reductions in body fat and serum HDL-cholesterol compared to the control group.68 Furthermore, in a 6 months interventional program that was focused on stimulating mild to moderate physical activity in Japanese elderly, a reduction in serum sRAGE was demonstrated. The decrease in sRAGE levels could be explained by a reduction of plasma AGEs, which in its turn can inactivate RAGE expression as well as sRAGE circulation as a scavenger of AGEs.69 In contrast, moderate exercise for six months in type 2 diabetic women resulted in increased sRAGE levels and improved cardio-metabolic risk factors. This possibly improves scavenging of AGEs by sRAGE and decreases activation of the AGE-RAGE pathway, preventing cellular dysfunction.70 Since these studies show opposing effects, which might be due to the study population, the clinical relevance of the relationship between exercise and sRAGE should be studied further. Finally, in a 12-week study obese men participated in either a low AGE diet, physical (aerobic) exercise (45 minutes with an intensity of 65-75% of maximum heart rate, three times a week) or a combination of both. In contrast to the other studies, an AGE-reducing effect of performing exercise alone was not perceived. Only in combination with the low AGE diet, this intervention provided a decrease in serum CML and MG.71
NutraceuticalsInstead of synthetic pharmaceuticals, compounds from natural sources have attracted attention to inhibit AGEs. Natural AGE inhibitors can be found in vegetables, fruit, tea and medicinal plants and many of them are available as dietary supplements.
Vitamin B and derivatives It has been reported that diabetic patients have a substantial deficiency of vitamin B1.72 Vitamin B6 (pyridoxamine and pyridoxine) and vitamin B1 (thiamine and the synthetic prodrug benfotiamine) supplementation have been described as a potent AGE inhibitory strategy. Pyridoxamine can inhibit the conversion of Amadori products to AGEs and is able to scavenge reactive oxygen species and
the reactive carbonyl intermediates that are products of sugar and lipid degradation.73 Although in vivo experiments demonstrated the efficient inhibition of AGEs by pyridoxamine along with positive effects on diabetic nephropathy,74 clinical evidence is more ambiguous. In 2007, a phase 2 trial including patients with kidney disease due to type 1 or 2 diabetes, showed the inhibiting effect of pyridoxamine treatment (Pyridorin; NephroGenex, Inc.) on plasma AGEs. Additionally, 6 month pyridoxamine treatment suggested the potential to slow down renal disease by a reduced change in serum creatinine from baseline and urinary TGFβ excretion.75 In contrast, a second trial in patients with type 2 diabetic nephropathy could not repeat this effect on creatinine, although patients with less renal impairment might profit. It is suggested that the effect of AGE inhibition is more effective in an earlier stage, which may be before the onset of pathologic changes.76 The effect of high-dose thiamine (vitamin B1) therapy was examined in a pilot study with type 2 diabetic patients with microalbuminuria, and reported decreased urinary albumin excretion after 3 months but no effect on dyslipidaemia, glycaemic control or blood pressure.77 Benfotiamine is a prodrug of thiamine with a higher bioavailability, and in vitro data indicates that it inhibits three major pathways that elicit hyperglycaemic vascular damage, among which the AGE formation pathway. Benfotiamine is able to inhibit these pathways simultaneously by increasing the activity of the transketolase enzyme. In addition, NF-κB activation could be prevented by benfotiamine. These effects were able to reduce diabetic retinopathy in an diabetic animal model.78 Human studies on benfotiamine are still inconclusive. Studies showing positive results include a beneficial effect on endothelial function, oxidative stress and AGE levels after consumption of a high AGE meal.79 Another study reported normalisation of several indicators of hyperglycaemia including AGE formation, although this last study only showed positive effects in combination with alpha-lipoic acid.80 Alternatively, Alkhalaf et al. concluded in two studies that benfotiamine treatment for 12 weeks did neither reduce urinary albumin excretion (UAE) and excretion of a tubular damage marker, nor did it affect plasma or urinary AGEs and plasma markers of endothelial dysfunction.81,82 Benfotiamine might be profitable for patients with diabetic polyneuropathy. In a double blind, placebo-controlled phase 3 trial, benfotiamine treatment for six weeks improved the Neuropathy Symptom Score (NSS) in the per protocol analysis, with the greatest improvement in the parameter pain.83 Other studies examined the effect of benfotiamine in combination with other B vitamins. A combination of benfotiamine with vitamin B6 and B12 for 12 weeks improved the nerve conduction velocity in the peroneal nerve, and this result was repeated in a 9 month intervention study in 9 patients.84 A different study on Milgamma-N (benfotiamine-vitamin B combination) reported therapeutic effects after six weeks on parameters pain and vibration sensation.85 However, these results were contradicted in a 24-month study examining the effect of benfotiamine (Benfogamma, Wörwag Pharma) in type 1 diabetic patients without clinical neuropathy. No beneficial effects on peripheral nerve function or inflammatory biomarkers were reported, which might be explained by differences in study population, where an improvement in patients with almost normal nerve function might be unfeasible.86
Fig. 3 The deleterious effects of AGEs can be stopped by reducing AGE accumulation and decrease RAGE signalling. There are several aspects in the AGE formation pathway that can be targeted by pharmaceutic, lifestyle and nutraceutical interventions.
CarnosineL-carnosine is a naturally occurring dipeptide that is primarily present in the central nervous system and skeletal muscles. In vitro studies demonstrated an effective anti-glycosylating effect by reacting with RCS and inhibiting protein crosslinking.87 Other protective functions of carnosine are its antioxidant activity by scavenging of reactive oxygen species.88 The results obtained from in vitro studies make carnosine an interesting potential therapeutic agent. In contrast to rodents, humans possess the carnosinase enzyme, which can degrade carnosine through hydrolysis. Therefore, carnosinase-resistant derivatives such as D-carnosine and its more bioavailable prodrug D-carnosine-octylester (DCO) have been developed. D-carnosine has been proved to have the same efficiency as L-carnosine in quenching RCS and diminishes the development of renal disease and dyslipidaemia in obese Zucker rats.89 Moreover, treatment with DCO was able to protect diabetic mice from atherosclerosis and renal disease.90,91 Various other in vivo studies supported the nephro- and retinoprotective effect of carnosine treatment in diabetic animals.92 However, in two of these studies, the protective effects of carnosine could not be explained by the anti-oxidative and anti-glycation characteristics of carnosine, but were exerted through other mechanisms.93,94 In clinical studies, carnosine derivative N-acetylcarnosine has been investigated as a treatment for (glycation-induced) cataract. Eyedrops with 1% N-acetylcarnosine (Can-C™ Eye
Drops), which is more resistant to carnosinase than L-carnosine, improved vision in both subjects with cataract and without.95 The effect of carnosine on the skin has been examined as well, since SAF increases during aging and correlates with AGE deposition in the skin.10 AGEs induce apoptosis of dermal fibroblasts and crosslinking of collagen, leading to stiffness of the tissue.96 The subjects in this study were given supplements that combine L-carnosine with competitive carnosinase inhibitors to increase tissue L-carnosine levels without increasing its concentration in blood plasma (Can-C Plus, Innovative Vision Products, Inc., New Castle, DE, USA). Oral supplementation for three months had a positive influence on signs of skin aging, such as reduction of fine lines and improved skin appearance.97
PolyphenolsMany nutraceuticals are rich in polyphenols that possess anti-glycation activity through various mechanisms, such as regulation of glucose metabolism, antioxidant effects and inhibition of the Aldose Reductase (AR) pathway.98 AR is an enzyme in the polyol pathway and active/enhanced under hyperglycaemic conditions. The polyol pathway is an important source of diabetes-induced oxidative stress and the formation of reactive fructose and 3-DG that contribute to AGE accumulation.99
Epigallocatechin 3-gallate Epigallocatechin 3-gallate (EGCG) is the major polyphenol in tea that possesses anti-inflammatory and anti-cancer properties.100 In a diabetic mouse model, induced by a high fat
diet, EGCG proved to decrease AGE accumulation with 80% in kidney and 96% in heart. Furthermore blood glucose levels and weight gain induced by a high-fat diet were reduced and the formation of cataracts could be prevented or delayed.101 In another study mice were treated with low and high doses of EGCG three times a week. After seventeen weeks, mice receiving a high dose of EGCG showed a near reversal of weight gain, improved glucose control and inhibited AGE accumulation in plasma, liver, kidney and adipose tissue.102 In rats suffering from diabetic nephropathy, EGCG showed comparable results, ameliorating the decline of kidney function.103 Additionally, green tea extract that is enriched with EGCG increased sRAGE levels in plasma of T2DM patients. sRAGE acts as a decoy for AGEs, preventing their interaction with RAGE.104 Simultaneously, EGCG-rich green tea extract decreased RAGE ligand S100A12, which indicates EGCG is able to block RAGE-ligand signalling, and could possibly prevent the progression of inflammatory responses that lead to the complications in diabetes.105 Although these results suggest the AGE inhibitory potential of the green tea derived EGCG, clinical studies are needed to show whether this could be a useful intervention for the treatment of diabetic complications. Examining the pharmacokinetics and safety issues is of great importance, since the dose used in in vivo studies far exceeds the amount of active substance in dietary supplements. Moreover, EGCG has been shown to have a low bioavailability, which led to the design of lipophilized derivatives that demonstrated slightly improved AGE-inhibitory activity in vitro.106
Rutin Rutin is a dietary flavonoid that is present in fruits, vegetables, tea and wine. Rutin is metabolized to a range of compounds such as quercetin, 3,4-DHT and 3,4-DHPAA. Rutin, along with its metabolites, can inhibit glucose autoxidation, the formation of AGEs and glycation of collagen.107 Its anti-glycation capacity was again demonstrated on goat eye lens proteins, indicating rutins potential to scavenge free radicals and chelating metal ions. The inhibition of aldose reductase (AR) is another mechanism that explains the benefits of rutin.108 The lowering effect of rutin on collagen fluorescence in diabetic rats was first described by Odetti et al.109 Further in vivo studies demonstrated that G-rutin, a rutin glucose derivative, could reduce glycation of serum and kidney proteins and lipid peroxidation in diabetic rats.110 In addition, rutin had preventive effects on the development of diabetic nephropathy in rats. After 10 weeks not only the expression of AGEs and accumulation of collagen were significantly reduced, fasting glucose levels and oxidative stress were decreased as well. Furthermore, rutin treatment attenuated microalbuminuria and the thickness of the glomerular basement membrane.111 Other studies examining the effect of rutin on rats with streptozotocin (STZ)-induced diabetes showed a protective function against kidney damage by positively regulating matrix remodelling112 and improvement of hyperglycaemia and dyslipidemia, while liver and heart toxicity induced by diabetes were ameliorated.113 Hence, rutin supplementation might be a potential treatment for diabetic pathological conditions.
ResveratrolResveratrol has been described as a polyphenol that possesses anti-oxidant, anti-cancer, anti-inflammation and life extending effects.114 Besides these positive health effects, resveratrol showed the ability to inhibit AGE formation in vitro. Resveratrol acted as an inhibitor of α-amylase and α-glucosidase, which are enzymes that catalyse the degradation of carbohydrates.115 Inhibition of these enzymes modulates sugar release and postprandial hyperglycemia and could be used as a therapy to decrease the risk of diabetes complications.116
Two in vivo studies report that resveratrol treatment did not affect AGE levels in liver and kidney, which might be due to relative short exposure time. Nevertheless, resveratrol improved antioxidant status and decreased plasma glucose and RAGE expression in liver and kidney of diabetic rats.117,118 Moreover, resveratrol treatment reduces the NF-κB-RAGE signalling pathway, thereby ameliorating vasculopathy in diabetic rats.119 Furthermore, resveratrol can exert its beneficial effects on diabetic complications by inhibition of Aldose Reductase (AR), resulting in a decrease of AGE formation in the kidney and improvement of the glomerular filtration rate and renal function in diabetic rats. Since AR mediates the polyol levels that contribute to cataract formation, resveratrol is able to inhibit opacification of the lens.120 Palsamy et al. support that resveratrol is able to normalize AR activity, and additionally other polyol pathway enzymes such as sorbitol dehydrogenase and glyoxalase-I (Glo-I), which limits AGE formation and glycative damage to the kidneys.121 In a clinical study the effect of resveratrol and hesperetin on vascular function was observed. These dietary bioactive compounds demonstrated to be strong inducers of glyoxalase-I, that is responsible for the detoxification of RCS compound MG. Co-therapy of resveratrol and hesperetin, instead of individual administration, was able to improve fasting plasma glucose, oral glucose insulin sensitivity and arterial and renal function in obese subjects.122
ConclusionsAGEs build up in the body naturally during aging. Yet, excessive AGE accumulation can accelerate the aging process and induce tissue damage, which is most evident in tissues consisting of long-lived proteins such as skin, heart, muscles and joints. Furthermore, AGEs are key players in the development and progression of many chronic diseases such as diabetes mellitus, cardiovascular disease and renal disease, and their complications. Since AGE levels could represent biological age and have shown to be a good predictor of cardiovascular and diabetes complications, AGE measurements can provide new information about a subject’s health or to the current prognosis of diabetic patients. Consequently, the investigation of anti-AGE interventions has been of major interest the latest years. The complexity of AGE formation and interactions allow for interventions at different levels. The strategies that prevent AGE formation depend on different mechanisms such as antioxidant ability, scavenging of reactive carbonyl species and inhibition of aldose reductase. Pharmaceutical options show promising results, yet their clinical relevance is doubtful so far due to safety concerns. For individuals with high AGE levels but no clinical symptoms other interventions might be more effective. Lifestyle interventions such as a low AGE diet and physical exercise are easily to implement and show beneficial effects on plasma AGEs and reduce inflammation and oxidative stress. Nutraceuticals, derived from food sources and available
as dietary supplements, have mostly been investigated in pre-clinical studies. Many studies evaluated these compounds as potential anti-AGE therapeutics and showed positive effects on diabetic complications such as nephro- and retinopathy. Until now, clinical evidence is mostly lacking and should be evaluated in the future. The duration of the interventions that is required to show a beneficial effect on AGEs is uncertain and might depend on the part of the AGE formation pathway the intervention is aimed at. Due to the fact that AGE accumulation represents glycaemic memory, interventions against AGEs could have prolonged effects on health and prevention of diabetic complications.
References
1. Ramasamy, R. et al. Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation. Glycobiology 15, 16R–28R (2005).
2. Ahmed, N. Advanced glycation endproducts--role in pathology of diabetic complications. Diabetes Res. Clin. Pract. 67, 3–21 (2005).
3. Baynes, J. W. & Thorpe, S. R. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 48, 1–9 (1999).
4. Fu, M. X. et al. The advanced glycation end product, Nepsilon-(carboxymethyl)lysine, is a product of both lipid peroxidation and glycoxidation reactions. J. Biol. Chem. 271, 9982–9986 (1996).
5. Stirban, A., Gawlowski, T. & Roden, M. Vascular effects of advanced glycation endproducts: Clinical effects and molecular mechanisms. Mol. Metab. 3, 94–108 (2014).
6. Koschinsky, T. et al. Orally absorbed reactive glycation products (glycotoxins): an environmental risk factor in diabetic nephropathy. Proc. Natl. Acad. Sci. U. S. A. 94, 6474–6479 (1997).
7. URIBARRI, J. et al. Advanced Glycation End Products in Foods and a Practical Guide to Their Reduction in the Diet. J. Am. Diet. Assoc. 110, 911–16.e12 (2010).
8. Cerami, C. et al. Tobacco smoke is a source of toxic reactive glycation products. Proc. Natl. Acad. Sci. 94, 13915–13920 (1997).
9. Jin, K. Modern Biological Theories of Aging. Aging Dis. 1, 72–74 (2010).
10. Corstjens, H. et al. Glycation associated skin autofluorescence and skin elasticity are related to chronological age and body mass index of healthy subjects. Exp. Gerontol. 43, 663–667 (2008).
11. Xue, M., Rabbani, N. & Thornalley, P. J. Glyoxalase in ageing. Semin. Cell Dev. Biol. 22, 293–301 (2011).
12. Bierhaus, A. et al. Understanding RAGE, the receptor for advanced glycation end products. J. Mol. Med. Berl. Ger. 83, 876–886 (2005).
13. Lander, H. M. et al. Activation of the receptor for advanced glycation end products triggers a p21(ras)-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J. Biol. Chem. 272, 17810–17814 (1997).
14. Schmidt, A. M. et al. Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes. J. Clin. Invest. 96, 1395–1403 (1995).
15. Wautier, M. P. et al. Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. Am. J. Physiol. Endocrinol. Metab. 280, E685-694 (2001).
16. Sims, T. J., Rasmussen, L. M., Oxlund, H. & Bailey, A. J. The role of glycation cross-links in diabetic vascular stiffening. Diabetologia 39, 946–951 (1996).
17. Monnier, V. M. et al. Cross-Linking of the Extracellular Matrix by the Maillard Reaction in Aging and Diabetes: An Update on ‘a Puzzle Nearing Resolution’. Ann. N. Y. Acad. Sci. 1043, 533–544 (2005).
18. McNulty, M., Mahmud, A. & Feely, J. Advanced glycation end-products and arterial stiffness in hypertension. Am. J. Hypertens. 20, 242–247 (2007).
19. Beckman, J. A., Creager, M. A. & Libby, P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 287, 2570–2581 (2002).
20. Vlassara, H. Recent progress in advanced glycation end products and diabetic complications. Diabetes 46 Suppl 2, S19-25 (1997).
21. Bucala, R., Tracey, K. J. & Cerami, A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J. Clin. Invest. 87, 432–438 (1991).
22. Frank, R. N. On the pathogenesis of diabetic retinopathy. A 1990 update. Ophthalmology 98, 586–593 (1991).
23. Stitt, A. W. The role of advanced glycation in the pathogenesis of diabetic retinopathy. Exp. Mol. Pathol. 75, 95–108 (2003).
24. Monnier, V. M. et al. Maillard reaction-mediated molecular damage to extracellular matrix and other tissue proteins in diabetes, aging, and uremia. Diabetes 41 Suppl 2, 36–41 (1992).
25. Yamagishi, S., Fukami, K., Ueda, S. & Okuda, S. Molecular mechanisms of diabetic nephropathy and its therapeutic intervention. Curr. Drug Targets 8, 952–959 (2007).
26. Genuth, S. et al. Glycation and carboxymethyllysine levels in skin collagen predict the risk of future 10-year progression of diabetic retinopathy and nephropathy in the diabetes control and complications trial and epidemiology of diabetes interventions and complications participants with type 1 diabetes. Diabetes 54, 3103–3111 (2005).
27. Holman, R. R., Paul, S. K., Bethel, M. A., Matthews, D. R. & Neil, H. A. W. 10-year follow-up of intensive glucose control in type 2 diabetes. N. Engl. J. Med. 359, 1577–1589 (2008).
28. Gerrits, E. G. et al. Skin autofluorescence: a tool to identify type 2 diabetic patients at risk for developing microvascular complications. Diabetes Care 31, 517–521 (2008).
29. Lutgers, H. L. et al. Skin autofluorescence provides additional information to the UK Prospective Diabetes Study (UKPDS) risk score for the estimation of cardiovascular prognosis in type 2 diabetes mellitus. Diabetologia 52, 789–797 (2009).
30. Thornalley, P. J., Yurek-George, A. & Argirov, O. K. Kinetics and mechanism of the reaction of aminoguanidine with the alpha-oxoaldehydes glyoxal, methylglyoxal, and 3-deoxyglucosone under physiological conditions. Biochem. Pharmacol. 60, 55–65 (2000).
31. Bolton, W. K. et al. Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am. J. Nephrol. 24, 32–40 (2004).
32. Freedman, B. I. et al. Design and baseline characteristics for the aminoguanidine Clinical Trial in Overt Type 2 Diabetic Nephropathy (ACTION II). Control. Clin. Trials 20, 493–510 (1999).
33. Kass, D. A. et al. Improved arterial compliance by a novel advanced glycation end-product crosslink breaker. Circulation 104, 1464–1470 (2001).
34. Zieman, S. J. et al. Advanced glycation endproduct crosslink breaker (alagebrium) improves endothelial function in patients with isolated systolic hypertension. J. Hypertens. 25, 577–583 (2007).
35. Little, W. C. et al. The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure. J. Card. Fail. 11, 191–195 (2005).
36. Hartog, J. W. L. et al. Effects of alagebrium, an advanced glycation endproduct breaker, on exercise tolerance and cardiac function in patients with chronic heart failure. Eur. J. Heart Fail. 13, 899–908 (2011).
37. Fujimoto, N. et al. Cardiovascular effects of 1 year of alagebrium and endurance exercise training in healthy older individuals. Circ. Heart Fail. 6, 1155–1164 (2013).
38. Oudegeest-Sander, M. H. et al. The effect of an advanced glycation end-product crosslink breaker and exercise training on vascular function in older individuals: a randomized factorial design trial. Exp. Gerontol. 48, 1509–1517 (2013).
39. Fang, F. et al. RAGE-dependent signaling in microglia contributes to neuroinflammation, Abeta accumulation, and impaired learning/memory in a mouse model of Alzheimer’s disease. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 24, 1043–1055 (2010).
40. Galasko, D. et al. Clinical trial of an inhibitor of RAGE-Aβ interactions in Alzheimer disease. Neurology 82, 1536–1542 (2014).
41. Rosen, W. G., Mohs, R. C. & Davis, K. L. A new rating scale for Alzheimer’s disease. Am. J. Psychiatry 141, 1356–1364 (1984).
42. Beisswenger, P. J., Howell, S. K., Touchette, A. D., Lal, S. & Szwergold, B. S. Metformin reduces systemic methylglyoxal levels in type 2 diabetes. Diabetes 48, 198–202 (1999).
43. Rabbani, N. et al. Increased glycation and oxidative damage to apolipoprotein B100 of LDL cholesterol in patients with type 2 diabetes and effect of metformin. Diabetes 59, 1038–1045 (2010).
44. Kimura, Y. et al. Atorvastatin decreases serum levels of advanced glycation endproducts (AGEs) in nonalcoholic steatohepatitis (NASH) patients with dyslipidemia: clinical usefulness of AGEs as a biomarker for the attenuation of NASH. J. Gastroenterol. 45, 750–757 (2010).
45. Nakamura, T. et al. Atorvastatin reduces proteinuria in non-diabetic chronic kidney disease patients partly via lowering serum levels of advanced glycation end products (AGEs). Oxid. Med. Cell. Longev. 3, 304–307 (2010).
46. Scharnagl, H. et al. The HMG-CoA reductase inhibitor cerivastatin lowers advanced glycation end products in patients with type 2 diabetes. Exp. Clin. Endocrinol. Diabetes Off. J. Ger. Soc. Endocrinol. Ger. Diabetes Assoc. 115, 372–375 (2007).
47. Cuccurullo, C. et al. Suppression of RAGE as a basis of simvastatin-dependent plaque stabilization in type 2 diabetes. Arterioscler. Thromb. Vasc. Biol. 26, 2716–2723 (2006).
48. Sebeková, K. et al. Effects of ramipril in nondiabetic nephropathy: improved parameters of oxidatives stress and potential modulation of advanced glycation end products. J. Hum. Hypertens. 17, 265–270 (2003).
49. Komiya, N., Hirose, H., Saisho, Y., Saito, I. & Itoh, H. Effects of 12-month valsartan therapy on glycation and oxidative stress markers in type 2 diabetic subjects with hypertension. Int. Heart. J. 49, 681–689 (2008).
50. Ono, Y., Mizuno, K., Takahashi, M., Miura, Y. & Watanabe, T. Suppression of advanced glycation and lipoxidation end products by angiotensin II type-1 receptor blocker candesartan in type 2 diabetic patients with essential hypertension. Fukushima J. Med. Sci. 59, 69–75 (2013).
51. Saha, S. A., LaSalle, B. K., Clifton, G. D., Short, R. A. & Tuttle, K. R. Modulation of advanced glycation end products by candesartan in patients with diabetic kidney disease--a dose-response relationship study. Am. J. Ther. 17, 553–558 (2010).
52. Engelen, L. et al. Irbesartan treatment does not influence plasma levels of the advanced glycation end products N(epsilon)(1-carboxymethyl)lysine and N(epsilon)(1-carboxyethyl)lysine in patients with type 2 diabetes and microalbuminuria. A randomized controlled trial. Nephrol. Dial. Transplant. Off. Publ. Eur. Dial. Transpl. Assoc. - Eur. Ren. Assoc. 26, 3573–3577 (2011).
53. Semba, R. D. et al. Dietary intake of advanced glycation end products did not affect endothelial function and inflammation in healthy adults in a randomized controlled trial. J. Nutr. 144, 1037–1042 (2014).
54. Birlouez-Aragon, I. et al. A diet based on high-heat-treated foods promotes risk factors for diabetes mellitus and cardiovascular diseases. Am. J. Clin. Nutr. 91, 1220–1226 (2010).
55. Luévano-Contreras, C., Garay-Sevilla, M. E., Wrobel, K., Malacara, J. M. & Wrobel, K. Dietary advanced glycation end products restriction diminishes inflammation markers and oxidative stress in patients with type 2 diabetes mellitus. J. Clin. Biochem. Nutr. 52, 22–26 (2013).
56. Macías-Cervantes, M. H. et al. Effect of an advanced glycation end product-restricted diet and exercise on metabolic parameters in adult overweight men. Nutr. Burbank Los Angel. Cty. Calif 31, 446–451 (2015).
57. Uribarri, J. et al. Restriction of dietary glycotoxins reduces excessive advanced glycation end products in renal failure patients. J. Am. Soc. Nephrol. JASN 14, 728–731 (2003).
58. Vlassara, H. et al. Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy. Proc. Natl. Acad. Sci. U. S. A. 99, 15596–15601 (2002).
59. Vlassara, H. et al. Protection against loss of innate defenses in adulthood by low advanced glycation end products (AGE) intake: role of the antiinflammatory AGE receptor-1. J. Clin. Endocrinol. Metab. 94, 4483–4491 (2009).
60. Mark, A. B. et al. Consumption of a diet low in advanced glycation end products for 4 weeks improves insulin sensitivity in overweight women. Diabetes Care 37, 88–95 (2014).
61. Uribarri, J. et al. Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of AGER1 and SIRT1. Diabetes Care 34, 1610–1616 (2011).
62. Gugliucci, A. et al. Short-term low calorie diet intervention reduces serum advanced glycation end products in healthy overweight or obese adults. Ann. Nutr. Metab. 54, 197–201 (2009).
63. Henle, T. AGEs in foods: do they play a role in uremia? Kidney Int.
Suppl. S145-147 (2003). doi:10.1046/j.1523-1755.63.s84.16.x64. Blair, S. N. & Morris, J. N. Healthy hearts--and the universal
benefits of being physically active: physical activity and health. Ann. Epidemiol. 19, 253–256 (2009).
65. Kondoh, Y., Kawase, M. & Ohmori, S. D-lactate concentrations in blood, urine and sweat before and after exercise. Eur. J. Appl. Physiol. 65, 88–93 (1992).
66. Couppé, C. et al. Life-long endurance running is associated with reduced glycation and mechanical stress in connective tissue. Age Dordr. Neth. 36, 9665 (2014).
67. Goon, J. A. et al. Effect of Tai Chi exercise on DNA damage, antioxidant enzymes, and oxidative stress in middle-age adults. J. Phys. Act. Health 6, 43–54 (2009).
68. Yoshikawa, T., Miyazaki, A. & Fujimoto, S. Decrease in serum levels of advanced glycation end-products by short-term lifestyle modification in non-diabetic middle-aged females. Med. Sci. Monit. Int. Med. J. Exp. Clin. Res. 15, PH65-73 (2009).
69. Kotani, K. et al. Influence of Physical Activity Intervention on Circulating Soluble Receptor for Advanced Glycation end Products in Elderly Subjects. J. Clin. Med. Res. 3, 252–257 (2011).
70. Choi, K. M. et al. Effects of exercise on sRAGE levels and cardiometabolic risk factors in patients with type 2 diabetes: a randomized controlled trial. J. Clin. Endocrinol. Metab. 97, 3751–3758 (2012).
71. Macías-Cervantes, M. H. et al. Effect of an advanced glycation end product-restricted diet and exercise on metabolic parameters in adult overweight men. Nutr. Burbank Los Angel. Cty. Calif 31, 446–451 (2015).
72. Thornalley, P. J. et al. High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease. Diabetologia 50, 2164–2170 (2007).
73. Voziyan, P. A. & Hudson, B. G. Pyridoxamine: the many virtues of a maillard reaction inhibitor. Ann. N. Y. Acad. Sci. 1043, 807–816 (2005).
74. Alderson, N. L. et al. The AGE inhibitor pyridoxamine inhibits lipemia and development of renal and vascular disease in Zucker obese rats. Kidney Int. 63, 2123–2133 (2003).
75. Williams, M. E. et al. Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy. Am. J. Nephrol. 27, 605–614 (2007).
76. Lewis, E. J. et al. Pyridorin in type 2 diabetic nephropathy. J. Am. Soc. Nephrol. JASN 23, 131–136 (2012).
77. Rabbani, N. et al. High-dose thiamine therapy for patients with type 2 diabetes and microalbuminuria: a randomised, double-blind placebo-controlled pilot study. Diabetologia 52, 208–212 (2009).
78. Hammes, H.-P. et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat. Med. 9, 294–299 (2003).
79. Stirban, A. et al. Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes. Diabetes Care 29, 2064–2071 (2006).
80. Du, X., Edelstein, D. & Brownlee, M. Oral benfotiamine plus alpha-lipoic acid normalises complication-causing pathways in type 1 diabetes. Diabetologia 51, 1930–1932 (2008).
81. Alkhalaf, A. et al. A double-blind, randomized, placebo-controlled clinical trial on benfotiamine treatment in patients with diabetic nephropathy. Diabetes Care 33, 1598–1601 (2010).
82. Alkhalaf, A. et al. Effect of benfotiamine on advanced glycation endproducts and markers of endothelial dysfunction and inflammation in diabetic nephropathy. PloS One 7, e40427 (2012).
83. Stracke, H., Gaus, W., Achenbach, U., Federlin, K. & Bretzel, R. G. Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised, double blind, placebo-controlled clinical study. Exp. Clin. Endocrinol. Diabetes Off. J. Ger. Soc. Endocrinol. Ger. Diabetes Assoc. 116, 600–605 (2008).
84. Stracke, H., Lindemann, A. & Federlin, K. A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy. Exp. Clin. Endocrinol. Diabetes Off. J. Ger. Soc. Endocrinol. Ger. Diabetes Assoc. 104, 311–316 (1996).
85. Winkler, G. et al. Effectiveness of different benfotiamine dosage regimens in the treatment of painful diabetic neuropathy. Arzneimittelforschung. 49, 220–224 (1999).
86. Fraser, D. A. et al. The effects of long-term oral benfotiamine supplementation on peripheral nerve function and inflammatory markers in patients with type 1 diabetes: a 24-month, double-blind, randomized, placebo-controlled trial. Diabetes Care 35, 1095–1097 (2012).
87. Hipkiss, A. R. Carnosine, a protective, anti-ageing peptide? Int. J. Biochem. Cell Biol. 30, 863–868 (1998).
88. Boldyrev, A. A. Does carnosine possess direct antioxidant activity? Int. J. Biochem. 25, 1101–1107 (1993).
89. Aldini, G. et al. The carbonyl scavenger carnosine ameliorates dyslipidaemia and renal function in Zucker obese rats. J. Cell. Mol. Med. 15, 1339–1354 (2011).
90. Menini, S. et al. D-Carnosine octylester attenuates atherosclerosis and renal disease in ApoE null mice fed a Western diet through reduction of carbonyl stress and inflammation. Br. J. Pharmacol. 166, 1344–1356 (2012).
91. Menini, S., Iacobini, C., Ricci, C., Blasetti Fantauzzi, C. & Pugliese, G. Protection from diabetes-induced atherosclerosis and renal disease by D-carnosine-octylester: effects of early vs late inhibition of advanced glycation end-products in Apoe-null mice. Diabetologia 58, 845–853 (2015).
92. Peters, V. et al. Carnosine treatment in combination with ACE inhibition in diabetic rats. Regul. Pept. 194–195, 36–40 (2014).
93. Pfister, F. et al. Oral carnosine supplementation prevents vascular damage in experimental diabetic retinopathy. Cell. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharmacol. 28, 125–136 (2011).
94. Riedl, E. et al. Carnosine prevents apoptosis of glomerular cells and podocyte loss in STZ diabetic rats. Cell. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharmacol. 28, 279–288 (2011).
95. Babizhayev, M. A., Micans, P., Guiotto, A. & Kasus-Jacobi, A. N-acetylcarnosine lubricant eyedrops possess all-in-one universal antioxidant protective effects of L-carnosine in aqueous and lipid membrane environments, aldehyde scavenging, and transglycation activities inherent to cataracts: a clinical study of the new vision-saving drug N-acetylcarnosine eyedrop therapy in a database population of over 50,500 patients. Am. J. Ther. 16, 517–533 (2009).
96. Alikhani, Z. et al. Advanced glycation end products enhance expression of pro-apoptotic genes and stimulate fibroblast apoptosis through cytoplasmic and mitochondrial pathways. J. Biol. Chem. 280, 12087–12095 (2005).
97. Babizhayev, M. A., Deyev, A. I., Savel’yeva, E. L., Lankin, V. Z. & Yegorov, Y. E. Skin beautification with oral non-hydrolized versions of carnosine and carcinine: Effective therapeutic management and cosmetic skincare solutions against oxidative glycation and free-radical production as a causal mechanism of diabetic complications and skin aging. J. Dermatol. Treat. 23, 345–384 (2012).
98. Khangholi, S., Majid, F. A. A., Berwary, N. J. A., Ahmad, F. & Aziz, R. B. A. The Mechanisms of Inhibition of Advanced Glycation End Products Formation through Polyphenols in Hyperglycemic Condition. Planta Med. 82, 32–45 (2016).
99. Tsukushi, S. et al. Increased erythrocyte 3-DG and AGEs in diabetic hemodialysis patients: role of the polyol pathway. Kidney Int. 55, 1970–1976 (1999).
100. Lambert, J. D., Sang, S., Hong, J. & Yang, C. S. Anticancer and Anti-inflammatory Effects of Cysteine Metabolites of the Green Tea Polyphenol, (−)-Epigallocatechin-3-gallate. J. Agric. Food Chem. 58, 10016–10019 (2010).
101. Sampath, C., Sang, S. & Ahmedna, M. In vitro and in vivo inhibition of aldose reductase and advanced glycation end products by phloretin, epigallocatechin 3-gallate and [6]-gingerol. Biomed. Pharmacother. Biomedecine Pharmacother. 84, 502–513 (2016).
102. Sampath, C., Rashid, M. R., Sang, S. & Ahmedna, M. Green tea epigallocatechin 3-gallate alleviates hyperglycemia and reduces advanced glycation end products via nrf2 pathway in mice with high fat diet-induced obesity. Biomed. Pharmacother.
Biomedecine Pharmacother. 87, 73–81 (2016).103. Yamabe, N., Yokozawa, T., Oya, T. & Kim, M. Therapeutic potential
of (-)-epigallocatechin 3-O-gallate on renal damage in diabetic nephropathy model rats. J. Pharmacol. Exp. Ther. 319, 228–236 (2006).
104. Vazzana, N., Santilli, F., Cuccurullo, C. & Davì, G. Soluble forms of RAGE in internal medicine. Intern. Emerg. Med. 4, 389–401 (2009).
105. Huang, S.-M. et al. EGCG-rich green tea extract stimulates sRAGE secretion to inhibit S100A12-RAGE axis through ADAM10-mediated ectodomain shedding of extracellular RAGE in type 2 diabetes. Mol. Nutr. Food Res. 57, 2264–2268 (2013).
106. Wang, M., Zhang, X., Zhong, Y. J., Perera, N. & Shahidi, F. Antiglycation activity of lipophilized epigallocatechin gallate (EGCG) derivatives. Food Chem. 190, 1022–1026 (2016).
107. Cervantes-Laurean, D. et al. Inhibition of advanced glycation end product formation on collagen by rutin and its metabolites. J. Nutr. Biochem. 17, 531–540 (2006).
108. Muthenna, P., Akileshwari, C., Saraswat, M. & Bhanuprakash Reddy, G. Inhibition of advanced glycation end-product formation on eye lens protein by rutin. Br. J. Nutr. 107, 941–949 (2012).
109. Odetti, P. R., Borgoglio, A., De Pascale, A., Rolandi, R. & Adezati, L. Prevention of diabetes-increased aging effect on rat collagen-linked fluorescence by aminoguanidine and rutin. Diabetes 39, 796–801 (1990).
110. Nagasawa, T. et al. Dietary G-rutin suppresses glycation in tissue proteins of streptozotocin-induced diabetic rats. Mol. Cell. Biochem. 252, 141–147 (2003).
111. Hao, H. et al. Preventive effects of rutin on the development of experimental diabetic nephropathy in rats. Life Sci. 91, 959–967 (2012).
112. Kamalakkannan, N. & Stanely Mainzen Prince, P. The influence of rutin on the extracellular matrix in streptozotocin-induced diabetic rat kidney. J. Pharm. Pharmacol. 58, 1091–1098 (2006).
113. Fernandes, A. A. H. et al. Influence of rutin treatment on biochemical alterations in experimental diabetes. Biomed. Pharmacother. Biomedecine Pharmacother. 64, 214–219 (2010).
114. Yang, T., Wang, L., Zhu, M., Zhang, L. & Yan, L. Properties and molecular mechanisms of resveratrol: a review. Pharm. 70, 501–506 (2015).
115. Shen, Y., Xu, Z. & Sheng, Z. Ability of resveratrol to inhibit advanced glycation end product formation and carbohydrate-hydrolyzing enzyme activity, and to conjugate methylglyoxal. Food Chem. 216, 153–160 (2017).
116. Thilagam, E., Parimaladevi, B., Kumarappan, C. & Mandal, S. C. α-Glucosidase and α-amylase inhibitory activity of Senna surattensis. J. Acupunct. Meridian Stud. 6, 24–30 (2013).
117. Khazaei, M. et al. Effects of Resveratrol on Receptor for Advanced Glycation End Products (RAGE) Expression and Oxidative Stress in the Liver of Rats with Type 2 Diabetes. Phytother. Res. PTR 30, 66–71 (2016).
118. Moridi, H. et al. Resveratrol-Dependent Down-regulation of Receptor for Advanced Glycation End-products and Oxidative Stress in Kidney of Rats With Diabetes. Int. J. Endocrinol. Metab. 13, e23542 (2015).
119. Jing, Y.-H., Chen, K.-H., Yang, S.-H., Kuo, P.-C. & Chen, J.-K. Resveratrol ameliorates vasculopathy in STZ-induced diabetic rats: role of AGE-RAGE signalling. Diabetes Metab. Res. Rev. 26, 212–222 (2010).
120. Ciddi, V. & Dodda, D. Therapeutic potential of resveratrol in diabetic complications: In vitro and in vivo studies. Pharmacol. Rep. PR 66, 799–803 (2014).
121. Palsamy, P. & Subramanian, S. Resveratrol protects diabetic kidney by attenuating hyperglycemia-mediated oxidative stress and renal inflammatory cytokines via Nrf2-Keap1 signaling. Biochim. Biophys. Acta 1812, 719–731 (2011).
122. Xue, M. et al. Improved Glycemic Control and Vascular Function in Overweight and Obese Subjects by Glyoxalase 1 Inducer Formulation. Diabetes 65, 2282–2294 (2016).
AGE Reader Key Publications
• Lifestyle and clinical determinants of skin autofluorescence in a population-based cohort study. van Waateringe R. et al. Eur J Clin Invest. 2016 Mar 22. Epub.
• Skin autofluorescence provides additional information to the UK Prospective Diabetes Study (UKPDS) risk score for the estimation of cardiovascular prognosis in type 2 diabetes mellitus. Lutgers H. et al, Diabetologia, 2009; 52(5): 789-797
• Skin autofluorescence and risk of micro- and macrovascular complications in patients with Type 2 diabetes mellitus-a multi-centre study. Noordzij M.J. et al. Diabet Med. 2012 Dec;29(12):1556-61.
• Skin Autofluorescence and the Association with Renal and Cardiovascular Risk Factors in Chronic Kidney Disease Stage 3. McIntyre N. et al. Clin J Am Soc Nephrol. 2011 Sep 1. Epub
• Skin Autofluorescence: A tool to identify type 2 diabetic patients at risk for developing microvascular disease. Gerrits E. et al. Diabetes Care. 2008; 31: 517-521
• Messung der Autofluoreszenz der Haut. Stirban A. and Heinemann L. Diabetes Stoffw Herz. 2013; 22 (full text available)
• Skin Autofluorescence Is Associated With 5-Year Mortality and Cardiovascular Events in Patients With Peripheral Artery Disease. de Vos LC. et al. Arterioscler Thromb Vasc Biol. 2014 Feb 13.
• Simple non-invasive assessment of advanced glycation endproducts accumulation. Meerwaldt R et al, Diabetologia, 2004; 47:1324-1330
AGE Reader in diabetes
1. Skin Autofluorescence is a Noninvasive Surrogate Marker for Diabetic Microvascular Complications and Carotid Intima-Media Thickness in Japanese Patients with Type 2 Diabetes: A Cross-sectional Study. Yoshioka K. Diabetes Ther. 2017 Nov 24. doi: 10.1007/s13300-017-0339-3.
2. Fokkens B.T. et al. Skin autofluorescence improves the Finnish Diabetes Risk Score in the detection of diabetes in a large population-based cohort: The LifeLines Cohort Study. Fokkens B. et al. Diabetes Metab. 2017 Oct 30. pii: S1262-3636(17)30513-X. doi: 10.1016/j.diabet.2017.09.002.
3. Ethnicity and skin autofluorescence-based risk-engines for cardiovascular disease and diabetes mellitus. Ahmad M.S. et al. PLoS One. 2017 Sep 20;12(9):e0185175.
4. Progression of skin autofluorescence of AGEs over 4 years in patients with type 1 diabetes. Rajaobelina K et al. Diabetes Metab Res Rev. 2017 Jul 18. doi: 10.1002/dmrr.2917.
5. The relationship between circulating irisin levels and tissues AGE accumulation in type 2 diabetes patients. Li Z. et al. Biosci Rep. 2017 Apr 13. doi: 10.1042/BSR20170213.
6. Vitreous advanced glycation endproducts and α-dicarbonyls in retinal detachment patients with type 2 diabetes mellitus and non-diabetic controls. Fokkens B.T. et al. PLoS One. 2017 Mar 6;12(3):e0173379. doi: 10.1371/journal.pone.0173379.
7. Skin autofluorescence, renal insufficiency and retinopathy in patients with type 2 diabetes. Bentata R. et al. J Diabetes Complications. 2016 Oct 30. [Epub ahead of print]
8. Association between small fiber neuropathy and higher skin accumulation of advanced glycation end products in patients with type 1 diabetes. Araszkiewicz A, et al. Pol Arch Med Wewn. 2016 Nov 22;126(11):847-853.
9. Risk factors for autonomic and somatic nerve dysfunction in different stages of glucose tolerance. Dimova R, et al. J Diabetes Complications. 2016 Nov 6. [Epub ahead of print]
10. Skin autofluorescence (a marker for advanced glycation end products) and erectile dysfunction in diabetes. Kouidrat Y. et al. J Diabetes Complications. 2016 Oct 29. pii: S1056-8727(16)30351-8. [Epub ahead of print]
11. Skin autofluorescence is increased in young people with type 1 diabetes exposed to secondhand smoking. Vollenbrock CE. et al. J Diabetes. 2016 Oct 27. (Epub).
12. Higher skin autofluorescence in young people with Type 1 diabetes and microvascular complications. Cho YH. et al. Diabet Med. 2016 Oct 22. (Epub)
13. Advanced glycation end products is a risk for muscle weakness in Japanese patients with type 1 diabetes. Mori H. et al. J Diabetes Investig. 2016 Oct 11. (Epub) (FULL TEXT available)
14. Skin Autofluorescence is Associated with Early-stage Atherosclerosis in Patients with Type 1 Diabetes. Osawa S et al. J Atheroscler Thromb. 2016 Sep 2.
15. Skin autofluorescence predicts cardio-renal outcome in type 1 diabetes: a longitudinal study. Vélayoudom-Céphise FL et al. Cardiovasc Diabetol. 2016 Sep 1;15(1):127.
16. Skin Autofluorescence and Pentosidine Are Associated With Aortic Stiffening: The Maastricht Study. van Eupen MG et al. Hypertension. 2016 Oct;68(4):956-63.
17. Skin fluorescence as a clinical tool for non-invasive assessment of advanced glycation and long-term complications of diabetes. Fokkens BT, Smit AJ. Glycoconj J. 2016 Aug;33(4):527-35.
18. ADVANCED GLYCATION END PRODUCT (AGE) ACCUMULATION IN THE SKIN IS ASSOCIATED WITH DEPRESSION: THE MAASTRICHT STUDY. van Dooren FE et al. Depress Anxiety. 2016 Jun 6. (Epub)
19. Skin autofluorescence and peripheral neuropathy four years later in type 1 diabetes. Rajaobelina K. et al. Diabetes Metab Res Rev. 2016 May 27. Epub
20. The relationship between advanced glycation endproducts and ocular circulation in type 2 diabetes. Hashimoto K. et al. J Diabetes Complications 2016 May 4. Epub.
21. Advanced Glycation Endproducts and Bone Material Strength in Type 2 Diabetes. Furst J.R. et al. J Clin Endocrinol Metab. 2016 Apr 26. Epub.
22. Association of Advanced Glycation End Products with coronary Artery Calcification in Japanese Subjects with Type 2 Diabetes as Assessed by Skin Autofluorescence. Hangai M. et al. J Atheroscler Thromb. 2016 Mar 10.
23. Non-invasive Measurement of Skin Autofluorescence as a Beneficial Surrogate Marker for Atherosclerosis in Patients with Type 2 Diabetes. Temma J. et al. J Med Invest. 2015;62(3-4):126-9.
24. Advanced glycation end products, measured in skin, vs. HbA1c in children with type 1 diabetes mellitus. Banser A. et al. Pediatr Diabetes. 2015 Sep 2.
25. Relationship between skin auto fluorescence and conventional glycemic markers in patients with diabetes. Mácsai E. et al. Orv Hetil. 2015 Aug 16;156(33):1341-7.
26. In diabetic Charcot neuroarthropathy impaired microvascular function is related to long lasting metabolic control and low grade inflammatory process. Araszkiewicz A. et al. Microvasc Res. 2015 Aug 1;101:143-147.
27. Vitamin D status is associated with skin autofluorescence in patients with type 2 diabetes mellitus: a preliminary report. Krul-Poel Y.H. et al. Cardiovasc Diabetol. 2015 Jul 16;14:89.
28. Is skin autofluorescence a marker of metabolic memory in pregnant women with diabetes? Maury E. et al. Diabet Med. 2015 May 16.
29. The Association Between Skin Autofluorescence and Vascular Complications in Chinese Patients With Diabetic Foot Ulcer: An Observational Study Done in Shanghai. Liu C. et al. Int J Low Extrem Wounds. 2015. (Epub)
30. Autofluorescence of Skin Advanced Glycation End Products: Marker of Metabolic Memory in Elderly Population. Rajaobelina K. et al. J Gerontol A Biol Sci Med Sci. 2015 Jan 14 (Epub)
31. Skin autofluorescence is associated with carotid intima-media thickness, diabetic microangiopathy, and long-lasting metabolic control in type 1 diabetic patients. Results from Poznan Prospective Study. Araszkiewicz A. et al. Microvasc Res. 2015 Jan 10 (Epub)
32. Association of advanced glycation end products and chronic kidney disease with macroangiopathy in type 2 diabetes. Rigalleau V. et al. J Diabetes Complications. 2014 Oct 30. Epub
33. Advanced glycation end products (AGEs) and the soluble receptor for AGE (sRAGE) in patients with type 1 diabetes and coeliac disease. Bakker S.F. et al. Nutr Metab Cardiovasc Dis. 2014 Nov 1.Epub
34. Associations of advanced glycation endproducts with cognitive functions in individuals with and without type 2 diabetes. Spauwen P.J. et al. J Clin Endocrinol Metab. 2014 Dec 2
35. Relationship of Skin Autofluorescence to Severity of Retinopathy in Type 2 Diabetes. Yasuda M. et al. Curr Eye Res. 2014 May 28:1-8.
36. Type 2 diabetes mellitus, skin autofluorescence and brain atrophy. Moran C. et al. Diabetes. 2014 Jul 22.
37. AGEs and chronic subclinical inflammation in diabetes: disorders of immune system. Hu H. et al. Diabetes Metab Res Rev. 2014 May 20. Epub
38. Correlation between diabetic makuls severity and elevated skin autofluorescence as a marker of advanced glycation end-product accumulation in type 2 diabetic patients. Hirano T. et al. J Diabetes Complications. 2014 Mar 10. Epub
39. Advanced glycation end products are associated with arterial stiffness in type 1 diabetes. Llauradó G. et al. J Endocrinol. 2014 Jun;221(3):405-13.
40. Messung der Autofluoreszenz der Haut. Stirban A. and Heinemann L. Diabetes Stoffw Herz. 2013; 22 (full text available)
41. Skin autofluorescence relates to soluble receptor for advanced glycation end-products and albuminuria in diabetes mellitus. Skrha J Jr. et al. J Diabetes Res. Epub 2013 Mar 10.
42. Skin autofluorescence based decision tree in detection of impaired glucose tolerance and diabetes. Smit AJ. et al. PLoS One. 2013 Jun 4;8(6):e65592.
43. Potential inhibitory effects of L-carnitine supplementation on tissue advanced glycation end products in patients with hemodialysis. Fukami K. Rejuvenation Res. 2013 Aug 4. [Epub ahead of print]
44. Skin autofluorescence relates to soluble receptor for advanced glycation end-products and albuminuria in diabetes mellitus. Skrha J Jr. et al. J Diabetes Res. 2013;2013:650694.
45. Skin autofluorescence is associated with past glycaemic control and complications in type 1 diabetes mellitus. Genevieve M. et al. Diabetes Metab. 2013 May 2. [Epub ahead of print]
46. Advanced Glycation End Products Assessed by Skin Autofluorescence-A New Marker of Diabetic Foot Ulceration. Vouillarmet J. et al. Diabetes Technol Ther. 2013 Apr 30. [Epub ahead of print]
47. Study design of DIACORE (DIAbetes COhoRtE) - a cohort study of patients with diabetes mellitus type 2. Dörhöfer L, BMC Med Genet. 2013 Feb 14;14:25.
48. Verification of Skin Autofluorescence Values by Mass Spectrometry in Adolescents with Type 1 Diabetes: Brief Report. Mácsai E. et al.Diabetes Technol Ther. 2013 Jan 23.
49. Advanced glycation end products in infant formulas do not contribute to insulin resistance associated with their consumption. Klenovics KS. et al.PLoS One. 2013;8(1):e53056.
50. Advanced Glycation End Products, Measured as Skin Autofluorescence, During Normal Pregnancy and Pregnancy Complicated by Diabetes Mellitus. de Ranitz-Greven WL. et al. Diabetes Technol Ther. 2012 Oct 31. (Epub)
51. Skin autofluorescence measurement in diabetological and nephrological clinical practice. Mácsai E. et al. Orv Hetil. 2012 Oct 21;153(42):1651-7.
52. Skin autofluorescence and risk of micro- and macrovascular complications in patients with Type 2 diabetes mellitus-a multi-centre study. Noordzij M.J. et al. Diabet Med. 2012 Aug 31. doi: 10.1111/dme.12005.
53. Advanced glycation end products measured by skin autofluorescence in a population with central obesity. den Engelsen C. et al. Dermatoendocrinol. 2012 Jan 1;4(1):33-8.
54. Elevated skin autofluorescence is strongly associated with foot ulcers in patients with diabetes: a cross-sectional, observational study of Chinese subjects. Hu H. et al. J Zhejiang Univ Sci B. 2012 May;13(5):372-7.
55. Advanced Glycation Endproducts and Diabetic Cardiovascular Disease. Prasad A. et al. Cardiol Rev. 2012 Feb 6. Epub
56. Non-invasive measures of tissue autofluorescence are increased in Type 1 diabetes complications and correlate with a non-invasive measure of vascular dysfunction. Januszewski A.S. et al. Diabet Med. 2011 Dec 28. doi: 10.1111/j.1464-5491.2011.03562.x.
57. Skin autofluorescence is associated with severity of vascular complications in Japanese patients with Type 2 diabetes. Tanaka K. et al. Diabet Med. 2011 Sep 14. Epub
58. Skin autofluorescence is inversely related to HDL anti-oxidative capacity in type 2 diabetes mellitus. Mulder D. et al. Atherosclerosis. 2011 May, Epub
59. Advanced Glycation End Products, Measured as Skin Autofluorescence, at Diagnosis in Gestational Diabetes Mellitus Compared with Normal Pregnancy. de Ranitz-Greven WL et al. Diabetes Technol Ther. 2011 Aug 29. Epub
60. Increased accumulation of skin advanced glycation end products is associated with microvascular complications in type 1 diabetes. Araszkiewicz A. et al. Diabetes Technol Ther. 2011 Aug;13(8):837-42.
61. Assessment of skin autofluorescence as a marker of advanced glycation end product accumulation in type 1 diabetes. Samborski P. et al. Pol Arch Med Wewn. 2011 Mar;121(3):67-72.
62. Advanced glycation end products, measured as skin autofluorescence and diabetes complications: a systematic review. Bos D.C. et al. Diabetes Technol Ther. 2011 Jul;13(7):773-9.
63. Tissue advanced glycation end products are associated with diastolic function and aerobic exercise capacity in diabetic heart failure patients. Willemsen S. et al. Eur J. Heart Fail 2010. doi:10.1093/eurjhf/hfq168
64. Skin autofluorescence and glycemic variability. Noordzij M. et al. Diabetes Technol Ther. 2010; 12(7): 581-585
65. Advanced glycation end products assessed by skin autofluorescence in type 1 diabetics are associated with nephropathy, but not retinopathy. Chabroux S. et al: Diabetes Metab, 2010 Apr;36(2):152-7.
66. Skin autofluorescence provides additional information to the UK Prospective Diabetes Study (UKPDS) risk score for the estimation of cardiovascular prognosis in type 2 diabetes mellitus Lutgers H. et al: Diabetologia, 2009; 52(5): 789-797
67. Skin Autofluorescence: A tool to identify type 2 diabetic patients at risk for developing microvascular disease. Gerrits E. et al. Diabetes Care. 2008; 31: 517-521
68. Skin autofluorescence is a strong predictor of cardiac mortality in diabetes Meerwaldt R, et al. Diabetes Care 2007, 30: 107-112
69. Skin autofluorescence in type 2 diabetes: Beyond blood glucose Monami M. et al. Diabetes Research & Clinical Practice July 2007. epub
70. Non-invasive AGE-measurements by skin autofluorescence in patients with Type 2 Diabetes Mellitus. Tool for risk-assessment of diabetes complications? Lutgers H, et al. Diabetes Care. 2006 Dec;29(12):2654-9
71. Increased accumulation of skin advanced glycation end-products precedes and correlates with clinical manifestation of diabetic neuropathy Meerwaldt R, et al. Diabetologia. 2005;48:1637-44.
72. The clinical relevance of advanced glycation endproducts (AGE) and recent developments in pharmaceutics to reduce AGE accumulation. Smit AJ, Lutgers HL.Curr Med Chem. 2004 Oct;11(20):2767-84.
AGE Reader in cardiovascular disease
73. Skin accumulation of advanced glycation end products is increased in patients with an abdominal aortic aneurysm. Boersema J. et al. J Vasc Surg. 2017 Jun 24. pii: S0741-5214(17)31144-8.
74. Impact of Hemorheology Assessed by the Microchannel Method on Pulsatility Index of the Common Carotid Artery in Patients With Type 2 Diabetes Mellitus. Hitsumoto T. et al. J Clin Med Res. 2017 Jul;9(7):579-585.
75. Diverging effects of diabetes mellitus in patients with peripheral artery disease and abdominal aortic aneurysm and the role of advanced glycation end-products: ARTERY study - protocol for a multicentre cross-sectional study. de Vos L.C. et al. BMJ Open. 2017 Apr 11;7(4):e012584. doi: 10.1136/bmjopen-2016-012584.
76. A Comparative Study on Skin and Plasma Advanced Glycation End Products and Their Associations with Arterial Stiffness. Liu C.Y. et al. Pulse (Basel). 2017 Jan;4(4):208-218.
77. Association of Skin Autofluorescence Levels With Kidney Function Decline in Patients With Peripheral Artery Disease. Schutte E et al. Arterioscler Thromb Vasc Biol. 2016 Aug;36(8):1709-14.
78. The Relationship Between Level of End-Products of Tissue Glycation and Pulse Wave Velocity in Non-diabetic Patients With Cardiovascular Disease. Ageev F.T. et al. Kardiologiia. 2015;55(6):63-7.
79. Skin autofluorescence as a measure of advanced glycation end products deposition predicts 5-year amputation in patients with peripheral artery disease. de Vos LC. et al. Arterioscler Thromb Vasc Biol. 2015 Jun;35(6):1532-7.
80. Evaluation of tissue accumulation levels of advanced glycation end products by skin autofluorescence: A novel marker of vascular complications in high-risk patients for cardiovascular disease. Yamagishi S.I. et al. Int J Cardiol. 2015 Mar (Epub)
81. Skin autofluorescence, 5-year mortality, and cardiovascular events in peripheral arterial disease: all that glitters is surely not gold. Schmidt AM. Arterioscler Thromb Vasc Biol. 2014 Apr;34(4):697-9.
82. Skin Autofluorescence Is Associated With 5-Year Mortality and Cardiovascular Events in Patients With Peripheral Artery Disease. de Vos LC. et al. Arterioscler Thromb Vasc Biol. 2014 Feb 13.
83. Skin Autofluorescence, a Non-Invasive Marker for AGE Accumulation, Is Associated with the Degree of Atherosclerosis. den Dekker MA. et al. PLoS One. 2013 Dec 23;8(12):e83084.
84. Skin autofluorescence as proxy of tissue AGE accumulation is dissociated from SCORE cardiovascular risk score, and remains so after 3 years. Tiessen AH. et al. Clin Chem Lab Med. 2013 Apr 2:1-7.
85. Skin Autofluorescence as a Measure of Advanced Glycation End Product Deposition Is Elevated in Peripheral Artery Disease. de Vos L.C. et al. Arterioscler Thromb Vasc Biol. 2012 Nov 8. (Epub)
86. Relationship between tissue glycation measured by autofluorescence and pulse wave velocity in young and elderly non-diabetic populations. Watfa G. et al. Diabetes Metab. 2012 Jun 13.
87. Advanced glycation end product associated skin autofluorescence: A mirror of vascular function? Hofmann B. et al. Exp Gerontol. 2012 May 12.
88. Effects of alagebrium, an advanced glycation endproduct breaker, on exercise tolerance and cardiac function in patients with chronic heart failure. Hartog J.W. et al. BENEFICIAL investigators. Eur J Heart Fail. 2011 Aug;13(8):899-908.
89. Skin autofluorescence is increased in patients with carotid artery stenosis and peripheral artery disease. Noordzij MJ. Int J Cardiovasc Imaging. 2011 Feb. Epub
90. Carotid artery intima media thickness associates with skin autofluoresence in non-diabetic subjects without clinically manifest cardiovascular disease. Lutgers H. et al. Eur J Clin Invest. 2010 ;40(9):812-7
91. Advanced glycation end-products, anti-hypertensive treatment and diastolic function in patients with hypertension and diastolic dysfunction. Hartog J. et al; Eur. Journal of Heart Failure, 2010 Apr;12(4):397-403
92. Advanced glycation end products in patients with cerebral infarction. Ohnuki Y. Intern Med. 2009;48(8):587-91.
93. Advanced Glycation End Products and their receptor RAGE in systemic autoimmune diseases - an inflamation propagating factor contributing to accelerated atherosclerosis. Nienhuis et al. Autoimmunity, 2009; 42(4): 302-304
94. Skin autofluorescence is elevated in acute myocardial infarction and is associated with the one-year incidence of major adverse cardiac events Mulder D. et al, Netherlands Heart Journal, Volume 17, Number 4, April 2009
95. Relation between food and drinking habits,and skin autofluorescence and intima media thickness in subjects at high cardiovascular risk Jochemsen M. et al: Journal of Food and Nutrition Research Vol. 48, 2009, No. 1, pp. 51–58
96. Advanced Glycation Endproducts (AGE) in chronic heart failure Smit A. et al. Annals of New York Academy of Science 2008; 1126:225-30
97. Clinical relevance of Advanced Glycation Endproducts for vascular surgery Meerwaldt R. et al. Eur J Vasc Endovasc Surg. 2008; 38,125-131
98. Skin autofluorescence is elevated in patients with stable coronary artery disease and is associated with serum levels of neopterin and the soluble receptor for advanced glycation end products. Mulder DJ. et al. Atherosclerosis. 2007:197:217-223
99. Clinical and prognostic value of Advanced Glycation End-products (AGEs) in chronic heart failure. Hartog J. et al Eur J Heart Failure 2007;9:1146-55
100. Skin Autofluorescence is an independent marker for Acute Myocardial Infarction Mulder DJ, et al. Circulation: 2005; 112:II-371.
AGE Reader in renal disease
101. Advanced glycation end-products (AGEs) accumulation in skin: relations with chronic kidney disease-mineral and bone disorder. França R.A. et al. J Bras Nefrol. 2017 Jul-Sep;39(3):253-260.
102. Skin autofluorescence in acute kidney injury. Lavielle A. et al. Crit Care. 2017 Feb 9;21(1):24.
103. Skin- and Plasmaautofluorescence in hemodialysis with glucose-free or glucose-containing dialysate. Ramsauer B, et al. BMC Nephrol. 2017 Jan 5;18(1):5.
104. Comparing changes in plasma and skin autofluorescence in low-flux versus high-flux hemodialysis. Ramsauer B. et al. Int J Artif Organs. 2015 (Epub)
105. Skin Autofluorescence Is Associated with Endothelial Dysfunction in Uremic Subjects on Hemodialysis. Wang CC. et al. PLoS One. 2016 Jan 25;11(1):e0147771.
106. Skin autofluorescence advanced glycosylation end products (AGEs) as an independent predictor of mortality in high flux haemodialysis and haemodialysis patients. Nongnuch A. et al. Nephrology (Carlton). 2015 May 25.
107. The effect of vegetarian diet on skin autofluorescence measurements in haemodialysis patients. Nongnuch A. et al. Br J Nutr. 2015 Mar 12:1-4. (Epub)
108. Skin Autofluorescence Is a Predictor of Cardiovascular Disease in Chronic Kidney Disease Patients. Furuya F. et al. Ther Apher Dial. 2014 Dec 29.
109. Tissue advanced glycation end products (AGEs), measured by skin autofluorescence, predict mortality in peritoneal dialysis. Siriopol D. et al. Int Urol Nephrol. 2014 Nov 26.
110. Skin autofluorescence as a novel marker of vascular damage in children and adolescents with chronic kidney disease. Makulska I. et al. Pediatr Nephrol. 2014 Nov 20.
111. Skin autofluorescence associates with vascular calcification in chronic kidney disease. Maku A.Y. et al. Arterioscler Thromb Vasc Biol. 2014 Aug;34(8):1784-90
112. Skin Autofluorescence and All-Cause Mortality in Stage 3 CKD. Fraser S.D. et al. Clin J Am Soc Nephrol. 2014 May 29. Epub
113. Skin Autofluorescence Predicts Cardiovascular Mortality in Patients on Chronic Hemodialysis. Kimura H. et al. Ther Apher Dial. 2014 Jan 24
114. Skin autofluorescence is associated with the progression of chronic kidney disease: a prospective observational study. Tanaka K. et al. PLoS One. 2013 Dec 12;8(12):e83799.
115. Skin and Plasma Autofluorescence During Hemodialysis: A Pilot Study. Graaff R. et al. Artif Organs. 2013 Oct 29.
116. Tissue Advanced Glycation End Product Deposition after Kidney Transplantation. Crowley LE et al. Nephron Clin Pract. 2013 Oct 15;124(1-2):54-59.
117. Advanced glycation end-products and skin autofluorescence in end-stage renal disease: a review. Arsov S. et al. Clin Chem Lab Med. 2013 Apr 4:1-10.
118. Accumulation of tissue advanced glycation end products correlated with glucose exposure dose and associated with cardiovascular morbidity in patients on peritoneal dialysis. Jiang J. et al. Atherosclerosis. 2012 Sep;224(1):187-94.
119. Skin autofluorescence as a marker of cardiovascular risk in children with chronic kidney disease. Siriopol I. et al. Pediatr Nephrol. 2012 Sep 15. (Epub)
120. Factors influencing skin autofluorescence of patients with peritoneal dialysis. Mácsai E. et al. Acta Physiol Hung. 2012 Jun;99(2):216-22.
121. Decreased serum carnitine is independently correlated with increased tissue accumulation levels of advanced glycation end products in hemodialysis patients. Adachi T. et al. Nephrology (Carlton). 2012 Jul 13. doi: 10.1111/j.1440-1797.2012.01642.x.
122. Skin Autofluorescence: A Pronounced Marker of Mortality in Hemodialysis Patients. Gerrits E. et al. Nephron Extra. 2012 Jan;2(1):184-191.
123. Advanced oxidation protein products and advanced glycation end products in children and adolescents with chronic renal insufficiency. Sebeková K. J Ren Nutr. 2012 Jan;22(1):143-8.
124. Evaluation of advanced glycation end products accumulation, using skin autofluorescence, in CKD and dialysis patients. Oleniuc M. et al. Int Urol Nephrol. 2011 Oct;44(5):1441-9.
125. Skin autofluorescence and the association with renal and cardiovascular risk factors in chronic kidney disease stage 3. McIntyre N.J. et al. Clin J Am Soc Nephrol. 2011 Oct;6(10):2356-63.
126. Tissue level of advanced glycation end products is an independent determinant of high-sensitivity C-reactive protein levels in haemodialysis patients. Nagano M. et al. Nephrology (Carlton). 2011 Mar;16(3):299-303
127. Skin autofluorescence as a measure of advanced glycation endproduct deposition: a novel risk marker in chronic kidney disease. Smit AJ. et al. Curr Opin Nephrol Hypertens, 2010: 19(6):527-33.
128. Skin autofluorescence is associated with renal function and cardiovascular diseases in pre-dialysis chronic kidney disease patients. Tanaka K. et al. Nephrol Dial Transplant. doi: 10.1093/ndt/gfq369
129. Advanced glycation end products, carotid atherosclerosis, and circulating endothelial progenitor cells in patients with end-stage renal disease. Ueno H et al. Metabolism, 2010, doi: 10.1016/j.metabol.2010.04.001
130. Tissue-Advanced Glycation End Product Concentration in Dialysis Patients McIntyre et al; CJASN, 2010; 5(1): 51-55
131. Does hepatitis C increase the accumulation of advanced glycation end products in haemodialysis patients? Arsov S. et al. Nephrol Dial Transplant 2009; 25(3): 885-891
132. Skin-Autofluorescence Is an Independent Predictor of Graft Loss in Renal Transplant Recipients Hartog J. et al, Transplantation • Volume 87, Number 7, April 15, 2009
133. Advanced Glycation End Products in Renal Failure: An Overview Noordzij M. et al, Journal of Renal Care 2008
134. AGEs, autofluorescence and renal failure Gerrits E. et al. Nephrology Dialysis and Transplantation November 25, 2008
135. Skin autofluorescence, a marker for advanced glycation end product accumulation, is associated with arterial stiffness in patients with end-stage renal disease Ueno H. et al: Metabolism Clinical and Experimental 57 (2008) 1452–1457
136. Skin Autofluorescence, a measure of tissue advanced glycation endproducts (AGEs), is related to the diastolic function of dialysis patients Hartog J. et al. Journal of Cardiac Failure. 2008; 14(7): 596-602
137. Risk factors for chronic transplant dysfunction and cardiovascular disease are related to accumulation of advanced glycation end-products in renal transplant recipients Hartog JWL, et al. Nephrol Dial Transpl 2006 Aug;21(8):2263-9
138. Skin autofluorescence, a measure of cumulative metabolic stress and advanced glycation endproducts, predicts mortality in hemodialysis patients Meerwaldt R, et al. J Am Soc Nephrol 2005;16:3687-93.
139. Skin autofluorescence, a noninvasive measure of advanced glycation end product accumulation, is a predictor of mortality in hemodialysis patients Meerwaldt R, et al. Ann N Y Acad Sci 2005;1043:911.
140. Accumulation of advanced glycation end products, measured as skin autofluorescence, in renal disease. Hartog JW. et al. Ann N Y Acad Sci. 2005 Jun;1043:299-307.
141. Advanced glycation endproducts in kidney transplant patients: a putative role in the development of chronic renal transplant dysfunction Hartog J. et al. Am J Kidn Dis 2004; 43:966-975
AGE Reader in other diseases
142. Autofluorescence of Skin Advanced Glycation End Products as a Risk Factor for Open Angle Glaucoma: The ALIENOR Study. Schweitzer C. et al. Invest Ophthalmol Vis Sci. 2018 Jan 1;59(1):75-84.
143. Association Between Accumulation of Advanced Glycation End-Products and Hearing Impairment in Community-Dwelling Older People: A Cross-Sectional Sukagawa Study. Niihata K. et al. J Am Med Dir Assoc. 2017 Nov 1. pii: S1525-8610(17)30520-0. doi: 0.1016/j.jamda.2017.09.008.
144. Accumulation of advanced glycation end products evaluated by skin autofluorescence and incident frailty in older adults from the Bordeaux Three-City cohort. Pilleron S. et al. PLoS One. 2017 Oct 17;12(10):e0186087.
145. Skin autofluorescence, a non-invasive biomarker for advanced glycation end products, is associated with the metabolic syndrome and its individual components. van Waateringe RP et al. Diabetol Metab Syndr. 2017 May 30;9:42.
146. Association between habitual dietary and lifestyle behaviours and skin autofluorescence (SAF), a marker of tissue accumulation of advanced glycation endproducts (AGEs), in healthy adults. Kellow NJ et al. Eur J Nutr. 2017 Jun 27. doi: 10.1007/s00394-017-1495-y.
147. Advanced Glycation End Products in Recent-Onset Psychosis Indicate Early Onset of Cardiovascular Risk. Hagen JM et al. J Clin Psychiatry. 2017 Apr 25. doi: 10.4088/JCP.16m10972.
148. Advanced glycation end-products in morbid obesity and after bariatric surgery: When glycemic memory starts to fail. Sánchez E. et al. Endocrinol Diabetes Nutr. 2017 Jan;64(1):4-10.
149. Advanced glycation end products as a biomarker for incisional hernia. Harlaar JJ et al. Hernia. 2017 Apr 12. doi: 10.1007/s10029-017-1610-2. [Epub ahead of print]
150. Advanced glycation end-products (AGEs) and associations with cardio-metabolic, lifestyle, and dietary factors in a general population: the NQplus study. Botros N. et al. Diabetes Metab Res Rev. 2017 Mar 1. doi: 10.1002/dmrr.2892.
151. Skin advanced glycation end-products evaluation in infants according to the type of feeding and mother's smoking habits. Federico G. et al. SAGE Open Med. 2016 Dec 9;4:2050312116682126. doi: 10.1177/2050312116682126.
152. Skin autofluorescence is associated with arterial stiffness and insulin level in endurance runners and healthy controls - Effects of aging and endurance exercise. Couppé C. et al. Exp Gerontol. 2017 May;91:9-14.
153. The association between skin autofluorescence and mean deviation in patients with open-angle glaucoma. Himori N, et al. Br J Ophthalmol. 2016 Dec 9.
154. Surface Area of Detachment, Proliferative Vitreoretinopathy, and Pulse Pressure, but not AGEs, are Associated With Retinal Redetachment. Fokkens BT et al. Invest Ophthalmol Vis Sci. 2016 Dec 1;57(15).
155. Skin Autofluorescence Examination as a Diagnostic Tool for Mild Cognitive Impairment in Healthy People. Igase M. et al. J Alzheimers Dis. 2016 Nov 14. [Epub ahead of print]
156. Skin advanced glycation end products in HIV infection are increased and predictive of development of cardiovascular events. Sprenger HG. et al. AIDS. 2016 Oct 18.
157. The Course of Skin and Serum Biomarkers of Advanced Glycation Endproducts and Its Association with Oxidative Stress, Inflammation, Disease Severity, and Mortality during ICU Admission in Critically Ill Patients: Results from a Prospective Pilot Study. Meertens JH et al. PLoS One. 2016 Aug 16;11(8). (FULL TEXT available)
158. Relationship between advanced glycation end-product accumulation and low skeletal muscle mass in Japanese men and women. Kato M. et al. Geriatr Gerontol Int. 2016 Apr 27. Epub.
159. Advanced glycation endproducts and their receptor in different body compartments in COPD. Hoonhorst S.J. et al. Respir Res. 2016 Apr 26; 17:46.
160. The association between systemic oxidative stress and ocular blood flow in patients with normal-tension glaucoma. Himori N. et al. Graefes Arch Clin Exp Ophthalmol. 2016 Feb;254(2):333-41.
161. Skin Autofluorescence in Systemic Sclerosis Is Related to the Disease and Vascular Damage: A Cross-Sectional Analytic Study of Comparative Groups. Dadoniene J. et al. Dis Markers. 2015;2015:837470. Epub
162. Traditional and emerging indicators of cardiovascular risk in chronic obstructive pulmonary disease. John M. et al. Chron Respir Dis. 2016 Mar 10.
163. A new gender-specific model for skin autofluorescence risk stratification. Ahmad M.S. et al. Sci Rep. 2015 May 14;5:10198.
164. Achilles tendons in people with type 2 diabetes show mildly compromised structure: an ultrasound tissue characterisation study. de Jonge S. et al. Br J Sports Med. 2015 Jan 13 (Epub)
165. Does reduction of disease activity improve early markers of cardiovascular disease in newly diagnosed rheumatoid arthritis patients? de Groot L. et al. Rheumatology (Oxford). 2015 Jan 12 (Epub)
166. Advanced glycation end products in the skin are enhanced in COPD. Hoonhorst S.J. et al. Metabolism. 2014 Jun 13. Epub
167. Life-long endurance running is associated with reduced glycation and mechanical stress in connective tissue. Couppé C. et. al. Age (Dordr). 2014 Aug;36(4):9665.
168. Plasma AGEs and skin autofluorescence are increased in COPD. Gopal P. et al. Eur Respir J. 2013 May 3. [Epub ahead of print]
169. Increased advanced glycation end-products (AGEs) assessed by skin autofluorescence in schizophrenia. Kouidrat Y. et al. J Psychiatr Res. 2013 Apr 21.
170. Local differences in skin autofluorescence may not reflect similar differences in oxidative stress exposure. Hettema M. et al. J Rheumatol. 2013 Feb;40(2):206.
171. Vascular Aspects of Fabry Disease in Relation to Clinical Manifestations and Elevations in Plasma Globotriaosylsphingosine. Rombach S.M. et al. Hypertension. 2012 Aug 6. (Epub)
172. Advanced Glycation Endproducts are increased in RA patients with controlled disease. de Groot L. et al. Arthritis Res Ther. 2011 Dec 14;13(6):R205.
173. Increased skin autofluorescence after colorectal operation reflects surgical stress and postoperative outcome. Pol H.W. et al. Am J Surg. 2011 Nov;202(5):583-9.
174. Skin autofluorescence, as marker of accumulation of advanced glycation endproducts and of cumulative metabolic stress, is not increased in patients with systemic sclerosis. Hettema M.E.. et al. Int J Rheumatol. 2011. Epub
175. Skin advanced glycation end-product accumulation is negatively associated with calcaneal osteo-sono assessment index among non-diabetic adult Japanese men. Momma H. Osteoporos Int. 2011 Sep 8. Epub
176. Skin autofluorescence is high in patients with cirrhosis - further arguing for the implication of Advanced Glycation End products. Maury E. et al. J Hepatol. 2011 May;54(5):1079-80.
177. Skin advanced glycation end product accumulation and muscle strength among adult men. Momma H. et al; Eur J Appl Physiol. 2010 (Epub)
178. Skin Autofluorescence as Marker of Tissue Advanced Glycation End-Products Accumulation in Formerly Preeclamptic Women. Coffeng S.M. et al. Hypertens Pregnancy; 2010, Epub
179. Accumulation of advanced glycation end (AGEs) products in intensive care patients: an observational, prospective study. Greven W. et al. BMC Clinical Pathology; 2010: 10 (4)
180. Increased accumulation of advanced glycation endproducts in patients with Wegener’s granulomatosis. Leeuw de K et al. Ann Rheum Dis. 2009; 69(3): 625-U191
181. Skin autofluorescence is increased in systemic lupus erythematosus but not reflected by plasma levels advanced glycation endproducts Nienhuis H. et al: Rheumatology. 2008; 47(10): 1554-1558
182. Skin autofluorescence is increased in systemic lupus erythematosus but not reflected by plasma levels of advanced glycation endproducts Nienhuis H. et al. Rheumatology; 2008; 47(10): 1554-1558
183. Advanced glycation end products and the absence of premature atherosclerosis in glycogen storage disease Ia den Hollander NC. et al. J Inherit Metab Dis. 2007. epub ahead of print
184. Accumulation of advanced glycation endproducts in patients with systemic lupus erythematosus. de Leeuw K. et al. Rheumatol 2007;45:1551-1556.
185. Skin autofluorescence, a marker of advanced glycation end products and oxidative stress, is increased in recently preelamptic women Blaauw J. et al. Am J Obstet Gynecol. 2006 Sep;195(3):717-22.
186. Enhanced skin autofluorescence as a marker for oxidative stress in sepsis, a pilot study. Mulder DJ, et al. Eur Soc Intensive Care Medicine 2004
AGE Reader (technical) validation
187. Association of advanced glycation end products, evaluated by skin autofluorescence, with lifestyle habits in a general Japanese population. Isami et al. J Int Med Res. 2018 Jan 1:300060517736914. doi:10.1177/0300060517736914.
188. The association between various smoking behaviors, cotinine biomarkers and skin autofluorescence, a marker for advanced glycation end product accumulation. van Waateringe RP et al. PLoS One. 2017 Jun 20;12(6):e0179330.
189. Skin autofluorescence, a non-invasive marker of advanced glycation end products: clinical relevance and limitations. Da Moura Semedo C. et al. Postgrad Med J. 2017 Jan 31. doi: 10.1136/postgradmedj-2016-134579.
190. Lifestyle and clinical determinants of skin autofluorescence in a population-based cohort study. van Waateringe R. et al. Eur J Clin Invest. 2016 Mar 22. Epub.
191. Body mass index, chronological age and hormonal status are better predictors of biological skin age than arm skin autofluorescence in healthy women who have never smoked. Randag A.C. et al. Br J Dermatol. 2015 Jul 25.
192. The skin autofluorescence reflects the posttranslational glycation grade of the matrix protein collagen. Jacobs K. et al. Free Radic Biol Med. 2014 Oct;75 Suppl 1:S34
193. GWAS identifies an NAT2 acetylator status tag single nucleotide polymorphism to be a major locus for skin fluorescence. Eny K.M. et al. Diabetologia. 2014 Aug;57(8):1623-34.
194. Reference values of skin autofluorescence as an estimation of tissue accumulation of advanced glycation end products in a general Slovak population. Klenovics KS, Diabet Med. 2013 Sep 30. doi: 10.1111/dme.12326. (Epub).
195. Reference values for the Chinese population of skin autofluorescence as a marker of advanced glycation end products accumulated in tissue. Yue X. et al. Diabet Med. 2011 Jul;28(7):818-23.
196. Dermal factors influencing measurement of skin autofluorescence. Noordzij M.J. et al. Diabetes Technol Ther. 2011 Feb;13(2):165-70
197. Skin color independent assessment of aging using skin autofluorescence Koetsier M. et al. Optics Express, 2010 ;18(14):14416-29
198. Reference Values of Skin Autofluorescence. Koetsier M. et al. Diabetes Technology & Therapeutics 2010; 12(5):399-403
199. Skin autofluorescence for the risk assessment of chronic complications in diabetes: a broad excitation range is sufficient Koetsier M. et al: Optics Express. 2009; 17(2): 509-519
200. Skin autofluorescence increases postprandially in human subjects Stirban A. et al. Diabetes Technology & Therapeutics 2008: 10:200-5
201. The Effect of Aggressive Versus Conventional Lipid-lowering Therapy on Markers of Inflammatory and Oxidative Stress. Mulder DJ. et al. Cardiovasc Drugs Ther. 2007 Apr;21(2):91-7.
202. Skin Autofluorescence, a Novel Marker for Glycation and Oxidative Stress derived Advanced Glycation Endproducts. An Overview of Current Clinical Studies, Evidence and Limitations Mulder DJ, et al. Diabetes Technology and Therapeutics 2006; 8.523-535.
203. Simple noninvasive measurement of skin autofluorescence Meerwaldt R, et al. Ann N Y Acad Sci. 2005;1043:290-298.
204. Instrumentation for the measurement of Autofluorescence in the human skin Graaff R et al. Proc. of SPIE Vol. 5692 (SPIE, Bellingham, WA, 2005). pp. 111-118.
205. Simple non-invasive assessment of advanced glycation endproducts accumulation Meerwaldt R et al. Diabetologia 2004; 47:1324-1330
For more information please visit: www.diagnoptics.com
www.age-reader.com